About GALNT12
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
GALNT12 c.5G>A, p.(Trp2Ter)
Classification
Likely pathogenic
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is likely pathogenic. Select a step to read what it means.
Likely pathogenic.A likely pathogenic classification under the recorded framework.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
LYFE Sciences is an AI system, and it can make mistakes.
Criteria may be applied incorrectly, sources may be misread, and a
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Double-check every criterion and its underlying evidence
before relying on any call.
01The reasoning
How it was classified
The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
Recorded applied criteria
The applied criteria and their strengths are shown as assessed under the stated framework.
Pathogenic evidence criteria: 2
Benign evidence criteria: 0
Pathogenic criteria applied · 2
PVS1Very strong
PVS1 · very strong
Nonsense variant NM_024642.5:c.5G>A (p.Trp2Ter) in exon 1 of 10, the MANE Select transcript of GALNT12, a gene with an established loss-of-function mechanism for germline cancer predisposition. The premature termination codon at amino acid position 2 is predicted to trigger nonsense-mediated decay, resulting in absence of functional protein. No evidence of alternative start codon rescue or non-critical exon involvement.
PM2Moderate
PM2 · moderate
The variant is present at extremely low frequency in population databases: gnomAD v2.1 overall AF=0.00341% (1/29,340 alleles, 0 homozygotes), maximum subpopulation AF=0.01178% (African/African American); gnomAD v4.1 overall AF=0.00052% (6/1,152,370 alleles, 0 homozygotes), maximum subpopulation AF=0.00658% (African/African American). All observed frequencies are well below the 0.1% PM2 threshold. Absent from gnomAD-Canada v1.0.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Likely pathogenic
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PVS1 very strong, PM2 moderate; combination = 1 very strong + 1 moderate, which maps to Likely Pathogenic.
02The sources
Evidence at a glance
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1
gnomAD v2.1
Population frequency
6 / 1,152,370 alleles
gnomAD v4.1: 6 / 1,152,370 alleles. Recorded AF 5.20666e-06. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.40832e-05; MAF= 0.00341%, 1/29340 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.000117841; MAF= 0.01178%, 1/8486 alleles, homozygotes = 0).
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.000 maximum delta
Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.
No listed criterion applied
SpliceAI ↗
ClinVar submissions
2 reported laboratory submissions
2 Uncertain significance. ClinVar API review status: criteria provided, multiple submitters, no conflicts.
Context only
ClinVar ↗
No screenshot for this evidence
Functional evidence
Not recorded
No standalone functional evidence summary is recorded in evidence_summary.functional.
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
No matching record reported
This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.
Context only
For specialists
Technical detail
ACMG/AMP criteria under Not recorded, with the data and sources behind each one.
26 criteria with recorded statuses: 2 met · 18 not met · 0 not assessed · 6 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
PVS1 (very_strong) met: NM_024642.5:c.5G>A is a nonsense variant (p.Trp2Ter) in exon 1 of the MANE Select transcript of GALNT12, a gene with an established loss-of-function mechanism for germline cancer predisposition. The premature stop at codon 2 is predicted to trigger nonsense-mediated decay.
PM2 (moderate) met: This variant is present at extremely low frequency in population databases (gnomAD v2.1 AF=0.00341%, v4.1 AF=0.00052%), well below the 0.1% threshold. No homozygotes observed in gnomAD.
The combination of PVS1 (very strong) and PM2 (moderate) results in a classification of Likely Pathogenic per generic ACMG/AMP 2015 criteria (Richards et al. 2015, PMID:25741868).
No criteria match.
Met · 2
PVS1 Very strongNonsense variant NM_024642.5:c.5G>A (p.Trp2Ter) in exon 1 of 10, the MANE Select transcript of GALNT12, a gene with an established loss-of-function mechanism for germline cancer predisposition. The premature termination codon at amino acid position 2 is predicted to trigger nonsense-mediated decay, resulting in absence of functional protein. No evidence of alternative start codon rescue or non-critical exon involvement. Details ▾Hide ▴
Evidence considered
- Null variant (nonsense) in gene where loss of function is a known mechanism of disease
- Variant located in exon 1/10
- premature stop at codon 2 predicted to trigger NMD
- GALNT12 germline LoF disease mechanism supported by literature (PMID:34278326
- PMID:37656691
- PMID:30886832
- PMID:39256447)
- MANE Select transcript NM_024642.5
- Generic PVS1 framework assessment per ClinGen SVI PMC6185798
Still missing
- Consider potential alternative translation initiation sites downstream of codon 2 that could produce N-terminally truncated protein
Sources
PM2 ModerateThe variant is present at extremely low frequency in population databases: gnomAD v2.1 overall AF=0.00341% (1/29,340 alleles, 0 homozygotes), maximum subpopulation AF=0.01178% (African/African American); gnomAD v4.1 overall AF=0.00052% (6/1,152,370 alleles, 0 homozygotes), maximum subpopulation AF=0.00658% (African/African American). All observed frequencies are well below the 0.1% PM2 threshold. Absent from gnomAD-Canada v1.0. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: AF=0.00341%
- 1/29
- 340 alleles
- 0 homozygotes
- gnomAD v4.1: AF=0.00052%
- 6/1
- 152
- 370 alleles
- Maximum subpopulation AF (African) = 0.01178%
- well below 0.1% PM2 threshold
- gnomAD-Canada v1.0: absent
Sources
Not met · 18 · evaluated, threshold not reached
PS2 No de novo occurrence with confirmed maternity and paternity was identified for this variant in any reviewed source. Details ▾Hide ▴
Still missing
- No trio or parent-of-origin data available
PS3 No well-established in vitro or in vivo functional studies demonstrating a damaging effect specific to NM_024642.5:c.5G>A were identified in the reviewed literature. Details ▾Hide ▴
Still missing
- No functional characterization of the p.Trp2Ter variant available
- experimental studies assessing NMD or protein expression could provide supporting evidence
PS4 The variant has been observed in one homozygous case (26-year-old female with grade 1 endometrioid endometrial carcinoma, PMID:30886832) and reported in one gastric adenocarcinoma case (PMID:32963463, per ClinVar submission SCV002655098). The prevalence in affected individuals does not reach statistical significance over general population frequency required for PS4. Details ▾Hide ▴
Evidence considered
- Homozygous observation in 26-year-old with G1 endometrioid endometrial carcinoma
- Reported in gastric adenocarcinoma patient per ClinVar audit
- gnomAD population frequency extremely low (v4.1 AF=0.00052%)
Still missing
- Case-control study with sufficient power to detect enrichment in cancer cohorts versus controls would be required to meet PS4
Sources
PM1 Variant does not lie within a statistically significant mutational hotspot (cancerhotspots.org negative), and no well-established critical or well-characterized functional domain has been defined at amino acid position 2 of GALNT12. Details ▾Hide ▴
Evidence considered
- Not in a statistically significant hotspot per cancerhotspots.org
- Codon 2 is in the N-terminal signal peptide/cytoplasmic tail region
- not a characterized catalytic domain
PM6 No de novo observation (without confirmation of maternity and paternity) was identified for this variant in any reviewed source. Details ▾Hide ▴
Still missing
- No de novo or presumed de novo reports available
PP1 No cosegregation data with disease in multiple affected family members are available for this variant. Details ▾Hide ▴
Still missing
- Family segregation studies not performed or not available
PP3 SpliceAI predicts no splicing impact (max delta score = 0.00). BayesDel score of 0.22007 is below commonly used pathogenic thresholds. REVEL score not available. In silico tools do not provide pathogenic support for this nonsense variant, and for premature termination variants, computational splicing predictors are not the primary pathogenic mechanism under assessment. Details ▾Hide ▴
Evidence considered
- SpliceAI: max delta = 0.00
- no predicted splice alteration
- BayesDel: 0.22007 (not in pathogenic range)
- REVEL: not available
Sources
spliceai ↗bayesdel
PP4 Although the variant has been observed in a 26-year-old homozygous patient with grade 1 endometrioid endometrial carcinoma (PMID:30886832) and in a gastric adenocarcinoma patient (PMID:32963463), these cancer phenotypes are not highly specific for GALNT12-related disease. GALNT12 is a moderate-penetrance cancer predisposition gene, and endometrial and gastric cancers have heterogeneous genetic etiologies. Details ▾Hide ▴
Evidence considered
- Homozygous variant in 26-year-old with G1 endometrioid endometrial carcinoma (PMID:30886832)
- Reported in gastric adenocarcinoma patient per ClinVar audit (PMID:32963463)
- Phenotype not highly specific for single-gene GALNT12 disorder
Still missing
- Homozygous LoF at very young age (26) in a cancer-predisposition gene is unusual
- clinical correlation with additional GALNT12-specific phenotypes would strengthen PP4
Sources
PP5 The variant is classified as Uncertain Significance in ClinVar (VariationID: 1061178) by two clinical laboratories (Ambry Genetics, Labcorp/Invitae). No reputable source has reported this variant as definitively pathogenic. Details ▾Hide ▴
Evidence considered
- ClinVar VariationID 1061178: Uncertain significance
- criteria provided
- single submitter (2 submitters)
Sources
BA1 The maximum population allele frequency is 0.01178% (African/African American, gnomAD v2.1), well below the 1% BA1 threshold. Does not meet stand-alone benign criterion. Details ▾Hide ▴
BS1 The maximum population allele frequency is 0.01178% (African/African American, gnomAD v2.1), well below the 0.3% BS1 threshold. Details ▾Hide ▴
Evidence considered
- Maximum gnomAD AF = 0.01178% (BS1 threshold = 0.3%)
Sources
BS2 No homozygous healthy adult carriers have been observed in population databases (gnomAD v2.1: 0 homozygotes; gnomAD v4.1: 0 homozygotes). The single homozygous observation was in a 26-year-old with endometrial carcinoma (PMID:30886832), not a healthy control. Details ▾Hide ▴
Evidence considered
- Zero homozygotes in gnomAD v2.1 and v4.1
- Homozygous observation in cancer-affected individual
- not healthy control
Sources
BS3 No well-established in vitro or in vivo functional studies demonstrating no damaging effect on protein function or splicing were identified for this variant. Details ▾Hide ▴
Still missing
- No functional studies available for this variant
BS4 No segregation data in affected families are available for this variant; BS4 requires lack of segregation in multiple affected family members. Details ▾Hide ▴
Still missing
- No family segregation data available
BP2 No evidence of this variant observed in trans with a known pathogenic variant in GALNT12. Observation in trans with a dominant pathogenic variant would support benign classification, but no such data exist. Details ▾Hide ▴
Still missing
- No phase data or trans-configuration data available
BP4 While SpliceAI predicts no splice impact (max delta score = 0.00), BP4 requires multiple lines of computational evidence suggesting no impact on gene product. For this nonsense variant, the primary pathogenic mechanism is protein truncation rather than splicing, and SpliceAI alone does not constitute multiple lines of benign evidence. BayesDel score of 0.22007 is not in the clearly benign range. Details ▾Hide ▴
Evidence considered
- SpliceAI: max delta = 0.00
- BayesDel: 0.22007 (not clearly benign)
Sources
spliceai ↗bayesdel
BP5 No cases have been identified where an alternate molecular basis for disease was found in an individual carrying this variant. Details ▾Hide ▴
Still missing
- No data on alternate molecular diagnoses in carriers
BP6 No reputable source has classified this variant as benign or likely benign. ClinVar classification is Uncertain Significance (VariationID: 1061178). Details ▾Hide ▴
Not applicable · 6· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/APS1 applies to missense variants where a different nucleotide change produces the same amino acid substitution previously established as pathogenic. Not applicable to nonsense variants. Details ▾Hide ▴
No further detail was recorded.
PM5 N/ANo same-residue comparator pathogenic missense variants were identified in ClinVar. PM5 candidates pipeline returned 0 candidates at codon 2; PM5 cannot be applied. Details ▾Hide ▴
Sources
pm5_candidates
PP2 N/APP2 applies to missense variants in genes with a low rate of benign missense variation where missense is a common mechanism of disease. This is a nonsense variant. Details ▾Hide ▴
No further detail was recorded.
BP1 N/ABP1 applies to missense variants in genes where truncating variants are the primary disease mechanism. This is a truncating (nonsense) variant. Details ▾Hide ▴
No further detail was recorded.
BP7 N/ABP7 applies to synonymous (silent) variants with no predicted splice impact. This is a nonsense variant. Details ▾Hide ▴
No further detail was recorded.
PS5 N/APS5 applies when a different nucleotide change at the same codon has been established as pathogenic; not applicable to nonsense variants at this codon as no alternative pathogenic missense has been established at codon 2. Details ▾Hide ▴
No further detail was recorded.
Identifiers
- Gene
- GALNT12
- Transcript
- NM_024642.5
- Coding (HGVS c.)
- NM_024642.5:c.5G>A
- Protein (HGVS p.)
- NP_078918.3:p.(Trp2Ter)
- GRCh38
- chr9:98807703 G>A
- GRCh37
- chr9:101569985 G>A
- ClinVar
- 1061178
Gene diagram
Every interpreted variant in GALNT12, mapped onto the exon structure of NM_024642.5. Select a row to find it on the plot.
GALNT12NM_024642.5
Fetching transcript structure from UCSC…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in GALNT12
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
6 / 1,152,370 alleles
AF 5.21e-06 · 0 homozygotes · FAF 2.24e-05
gnomAD v2.1
1 / 29,340 alleles
AF 3.41e-05 · 0 homozygotes
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 5.2e-06 · 6 / 1,152,370 alleles · 0 hom · FAF 2.2e-05
| African/African American4 / 60,752 | 6.6e-05 |
| Remaining individuals1 / 38,834 | 2.6e-05 |
| European (non-Finnish)1 / 938,514 | 1.1e-06 |
0 alternate alleles recorded in 7 other groups: Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish.
gnomAD v2.1
AF 3.4e-05 · 1 / 29,340 alleles · 0 hom
| African/African American1 / 8,486 | 0.00012 |
0 alternate alleles recorded in 7 other groups: Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), Remaining individuals, South Asian.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 5.20666e-06; MAF= 0.00052%, 6/1152370 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 6.58415e-05; MAF= 0.00658%, 4/60752 alleles, homozygotes = 0); grpmax FAF= 2.236e-05.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.40832e-05; MAF= 0.00341%, 1/29340 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.000117841; MAF= 0.01178%, 1/8486 alleles, homozygotes = 0).
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- Not available
- BayesDel
- 0.220
How the predictions were used
PP3 SpliceAI predicts no splicing impact (max delta score = 0.00). BayesDel score of 0.22007 is below commonly used pathogenic thresholds. REVEL score not available. In silico tools do not provide pathogenic support for this nonsense variant, and for premature termination variants, computational splicing predictors are not the primary pathogenic mechanism under assessment. Details ▾Hide ▴
Evidence considered
- SpliceAI: max delta = 0.00
- no predicted splice alteration
- BayesDel: 0.22007 (not in pathogenic range)
- REVEL: not available
Sources
spliceai ↗bayesdel
BP4 While SpliceAI predicts no splice impact (max delta score = 0.00), BP4 requires multiple lines of computational evidence suggesting no impact on gene product. For this nonsense variant, the primary pathogenic mechanism is protein truncation rather than splicing, and SpliceAI alone does not constitute multiple lines of benign evidence. BayesDel score of 0.22007 is not in the clearly benign range. Details ▾Hide ▴
Evidence considered
- SpliceAI: max delta = 0.00
- BayesDel: 0.22007 (not clearly benign)
Sources
spliceai ↗bayesdel
BP7 N/ABP7 applies to synonymous (silent) variants with no predicted splice impact. This is a nonsense variant. Details ▾Hide ▴
No further detail was recorded.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). BayesDel score = 0.22007.
2 paper records listed. 1 cited in the classification.
Cited in the classification
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PMID 30886832 ↗Genomic Comparison of Endometrioid Endometrial Carcinoma and Its Precancerous Lesions in Chinese Patients by High-Depth Next Generation Sequencing.Wang Y et al. · 2019NM_024642.5:c.5G>A (p.Trp2Ter) identified as a homozygous germline likely pathogenic variant in a 26-year-old Chinese female with grade 1 endometrioid endometrial carcinoma. No family history of cancer. Identified among 10 patients with pathogenic or likely pathogenic germline mutations in a cohort of 115 paired tumor-blood samples from patients with endometrial intraepithelial neoplasia and endometrioid endometrial carcinoma.→ PVS1 → PM2 Names this variant
Source detail
GALNT12 c.G5A (p.W2X) hom Likely pathogenic 26 G1 EEC None
Location Table 4 (Germline mutations); Results section 'Germline Mutations'; Discussion paragraph on germline findings
Context Targeted NGS panel of 363 cancer-related genes on paired fresh-frozen tumor and matched blood samples from 79 EEC and 36 EIN patients; tertiary hospital cohort (Peking Union Medical College Hospital, Beijing, China)
Other recorded publications
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PMID 32963463 ↗Characteristics of cancer susceptibility genes mutations in 282 patients with gastric adenocarcinoma.Ji K et al. · 2020NM_024642.5:c.5G>A reported in a patient with gastric adenocarcinoma, per ClinVar submission audit (SCV002655098, Ambry Genetics). The variant was identified in a cohort of 282 gastric adenocarcinoma patients screened with a 69-gene cancer susceptibility panel.Names this variant
Quoted passage
this variant has been reported in an individual with gastric adenocarcinoma and as homozygous in a chinese woman with endometrial cancer (ji k et al
Abstract and ClinVar submission evidence signal
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
6 / 1,152,370 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.000
Open source ↗
ClinVar
2 Uncertain significance
Open source ↗
COSMIC
Captured COSMIC source record
Open source ↗
Cancer hotspots
Captured Cancer Hotspots source record
Open source ↗
All source links
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/variation/1061178/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/9-101569985-G-A?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr9-98807703-G-A?dataset=gnomad_r4
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/9-98807703-G-A
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_024642.5%3Ac.5G%3…
- OncoKB ↗www.oncokb.org/gene/GALNT12/W2*
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=GALNT12+c.5G%3EA
- Cancer hotspots ↗www.cancerhotspots.org/
Statements for reports
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 5.20666e-06; MAF= 0.00052%, 6/1152370 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 6.58415e-05; MAF= 0.00658%, 4/60752 alleles, homozygotes = 0); grpmax FAF= 2.236e-05.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.40832e-05; MAF= 0.00341%, 1/29340 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.000117841; MAF= 0.01178%, 1/8486 alleles, homozygotes = 0).
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (2 clinical laboratories). (ClinVarID = 1061178)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). BayesDel score = 0.22007.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.