About MITF
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
MITF c.394C>A, p.(Gln132Lys)
Classification
Uncertain significance
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
Uncertain.The recorded classification is uncertain significance.
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
confident-looking classification can still be wrong.
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: 1
Benign evidence criteria: 1
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting
NM_198159.3:c.394C>A is absent from gnomAD-Canada and present at very low frequency in gnomAD v2.1 (AF=0.000198, 56/282,620 alleles) and v4.1 (AF=0.000126, 203/1,613,992 alleles), both below the 0.1% PM2 threshold. No homozygotes observed.
Benign criteria applied · 1
BP4Supporting
BP4 · supporting
Multiple in silico tools predict a benign effect for p.Gln132Lys. REVEL score is 0.26 (benign, well below 0.5 pathogenic threshold), BayesDel score is -0.0715 (benign), and SpliceAI predicts no splicing impact (max delta=0.05). All three independent computational predictors are concordant for a benign interpretation.
Recorded classification: Uncertain significance
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 supporting, BP4 supporting; combination = 1 supporting + 1 supporting benign, which maps to VUS.
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
203 / 1,613,992 alleles
gnomAD v4.1: 203 / 1,613,992 alleles. Recorded AF 0.000125775. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.000198146; MAF= 0.01981%, 56/282620 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.000403082; MAF= 0.04031%, 52/129006 alleles, homozygotes = 0); grpmax FAF= 0.0008586.
gnomAD-Canada
This variant is present in gnomAD-Canada v1.0 (AF= 0.00016290182450043442, 3/18416 alleles, homozygotes = 0).
SpliceAI score
0.050 maximum delta
Recorded SpliceAI maximum delta score: 0.050. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
7 reported laboratory submissions
7 Uncertain significance. ClinVar API review status: criteria provided, multiple submitters, no conflicts.
Context only
ClinVar ↗
Functional evidence
Statement recorded
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. MITF, a transcription factor involved in melanocyte differentiation, is altered by mutation and amplification in melanomas.
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 · 21 not met · 0 not assessed · 3 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
NM_198159.3:c.394C>A (p.Gln132Lys) is a missense variant in MITF exon 3. It is present at very low frequency in population databases (gnomAD v2.1 AF=0.0198%; v4.1 AF=0.0126%) with no homozygotes, meeting PM2 at supporting level.
Multiple in silico tools predict a benign effect: REVEL score 0.26 (benign), BayesDel score -0.0715 (benign), and SpliceAI max delta 0.05 (no predicted splicing impact), meeting BP4 at supporting level.
The variant has been classified as Uncertain Significance by 7 clinical laboratories in ClinVar (Variation ID: 493364). No functional studies, segregation data, or case-control evidence have been reported.
With one supporting pathogenic criterion (PM2) and one supporting benign criterion (BP4), the evidence is balanced and does not meet the threshold for Likely Pathogenic, Likely Benign, Pathogenic, or Benign. The variant is classified as Uncertain Significance.
No criteria match.
Met · 2
PM2 SupportingNM_198159.3:c.394C>A is absent from gnomAD-Canada and present at very low frequency in gnomAD v2.1 (AF=0.000198, 56/282,620 alleles) and v4.1 (AF=0.000126, 203/1,613,992 alleles), both below the 0.1% PM2 threshold. No homozygotes observed. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: AF=0.0198%
- 56/282
- 620 alleles
- 0 homozygotes
- gnomAD v4.1: AF=0.0126%
- 203/1
- 613
- 992 alleles
- gnomAD-Canada v1.0: absent
- Highest subpopulation: NFE AF=0.0403% (v2.1)
- still below 0.1% threshold
Sources
BP4 SupportingMultiple in silico tools predict a benign effect for p.Gln132Lys. REVEL score is 0.26 (benign, well below 0.5 pathogenic threshold), BayesDel score is -0.0715 (benign), and SpliceAI predicts no splicing impact (max delta=0.05). All three independent computational predictors are concordant for a benign interpretation. Details ▾Hide ▴
Evidence considered
- REVEL: 0.26 (benign)
- BayesDel: -0.0715 (benign)
- SpliceAI max delta: 0.05 (no predicted splicing alteration)
Sources
Not met · 21 · evaluated, threshold not reached
PVS1 NM_198159.3:c.394C>A is a missense variant (p.Gln132Lys). It does not fall into any default generic PVS1 null-variant bucket (nonsense, frameshift, or canonical ±1,2 splice consensus). PVS1 is not applicable to missense variants under the ClinGen SVI PVS1 decision framework (PMC6185798). Details ▾Hide ▴
Evidence considered
- Missense variant
- not a predicted null variant.
- Exon 3 missense outside canonical splice consensus.
Sources
PS1 No evidence of a different nucleotide change at the same codon resulting in the same amino acid substitution (Gln132Lys) with an established pathogenic classification. No PS1 comparator identified. Details ▾Hide ▴
Evidence considered
- No same-amino-acid pathogenic comparator variant identified in ClinVar or literature.
Still missing
- No ClinVar or literature search for alternate nucleotide changes producing p.Gln132Lys.
PS2 No de novo observation reported for NM_198159.3:c.394C>A. No confirmed maternity/paternity data available. Details ▾Hide ▴
Evidence considered
- No de novo data in ClinVar submissions or literature.
Still missing
- No trio or de novo sequencing data available.
PS3 No functional studies evaluating the biological effect of p.Gln132Lys have been identified. OncoKB classifies this variant as having Unknown Oncogenic Effect. ClinVar submissions explicitly note that functional studies have not confirmed any predicted effect. Details ▾Hide ▴
PS4 No case-control studies or statistically enriched observation in affected individuals versus controls have been reported for this variant. Details ▾Hide ▴
Evidence considered
- No case-control or cohort enrichment data available.
Still missing
- No affected versus control population statistics.
PM1 Residue Gln132 does not lie within a statistically significant mutational hotspot in MITF. Hotspot analysis shows no significant enrichment at this position. Details ▾Hide ▴
Evidence considered
- Residue-level hotspot analysis: not significant.
- Exact variant not listed in hotspot database.
PM6 No de novo observation reported for this variant with confirmed maternity and paternity. Details ▾Hide ▴
Evidence considered
- No de novo data found.
Still missing
- No trio or de novo sequencing data.
PP1 No segregation data available for this variant in affected families. Details ▾Hide ▴
Evidence considered
- No family segregation studies identified.
Still missing
- No cosegregation data in affected families.
PP2 Insufficient evidence that MITF has a low rate of benign missense variation and that missense variants are a common disease mechanism. MITF has both gain-of-function (p.Glu318Lys in melanoma) and loss-of-function mechanisms; missense constraint metrics are not available to support PP2. Details ▾Hide ▴
Evidence considered
- MITF disease mechanisms include both gain-of-function (melanoma susceptibility) and haploinsufficiency (Waardenburg syndrome type 2A).
- No gene-level missense Z-score or constraint metric available.
Still missing
- No missense constraint metric (e.g.
- gnomAD missense Z-score) available for MITF.
PP3 In silico tools do not support a deleterious effect. REVEL score is 0.26 (below the 0.5 threshold for pathogenicity), BayesDel score is -0.0715 (benign range), and SpliceAI predicts no splicing impact (max delta=0.05). All computational predictors favor a benign interpretation. Details ▾Hide ▴
Evidence considered
- REVEL: 0.26 (benign
- below 0.5 pathogenic threshold)
- BayesDel: -0.0715 (benign)
- SpliceAI max delta: 0.05 (no predicted splicing impact)
Sources
PP4 No patient phenotype data are available to evaluate whether the proband's clinical presentation is specific for MITF-related disease. Details ▾Hide ▴
Evidence considered
- No patient phenotype or clinical data provided.
Still missing
- No proband clinical history or phenotype specificity data.
PP5 No reputable source reports this variant as pathogenic. ClinVar classification is Uncertain Significance (7 clinical laboratories, single submitter review status). No expert panel has classified this variant as pathogenic. Details ▾Hide ▴
Evidence considered
- ClinVar: Uncertain significance
- criteria provided single submitter
- 7 clinical laboratories.
- No expert panel or reputable source reports this as pathogenic.
Sources
BA1 Maximum population allele frequency is 0.0403% in NFE (gnomAD v2.1), well below the 1% BA1 threshold. The variant is not common enough to be considered a standing benign polymorphism. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 max subpopulation AF: 0.0403% (NFE)
- gnomAD v4.1 max subpopulation AF: 0.0164% (NFE)
- Both well below 1% BA1 threshold
Sources
BS1 Maximum population allele frequency is 0.0403% in NFE (gnomAD v2.1), below the 0.3% BS1 threshold for a rare disease variant. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 max subpopulation AF: 0.0403% (NFE)
- below 0.3% threshold
- gnomAD v4.1 max subpopulation AF: 0.0164% (NFE)
Sources
BS2 Although this variant is observed in gnomAD (56 heterozygous alleles in v2.1, 203 in v4.1), no homozygous observations exist, and no observation in trans with a known pathogenic MITF variant has been reported. Without homozygous or in-trans data, BS2 cannot be applied under generic ACMG/AMP. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: 0 homozygotes
- gnomAD v4.1: 0 homozygotes
- No observation in trans with a pathogenic MITF variant
Still missing
- No homozygous or in-trans evidence to confirm benign presentation in a fully penetrant dominant disorder.
Sources
BS3 No well-established functional studies demonstrate that p.Gln132Lys has no deleterious effect on protein function. Details ▾Hide ▴
Evidence considered
- No benign functional evidence identified.
Still missing
- No in vitro or in vivo functional studies evaluating this variant.
BS4 No evidence of non-segregation with disease in affected families. Details ▾Hide ▴
Evidence considered
- No segregation or non-segregation data available.
Still missing
- No family studies to evaluate non-segregation.
BP1 BP1 applies when a missense variant occurs in a gene where only truncating variants cause disease. MITF has both missense (p.Glu318Lys in melanoma, Waardenburg syndrome type 2A missense variants) and truncating disease mechanisms. BP1 is not applicable. Details ▾Hide ▴
Evidence considered
- MITF disease mechanisms include missense variants (p.Glu318Lys melanoma susceptibility
- Waardenburg syndrome type 2A).
- Truncating mechanism is not the sole disease mechanism.
BP2 No observation of this variant in trans with a known pathogenic MITF variant. Details ▾Hide ▴
Evidence considered
- No in-trans observation data available.
Still missing
- No phase data with known pathogenic MITF variants.
BP5 No alternative molecular basis for disease has been identified in the proband. BP5 requires a different pathogenic variant in the same gene or a different gene explaining the phenotype. Details ▾Hide ▴
Evidence considered
- No alternative pathogenic variant reported in the case.
Still missing
- No proband genotype data to evaluate alternative molecular causes.
BP6 No reputable source reports this variant as benign. ClinVar classification is Uncertain Significance across 7 clinical laboratories. Details ▾Hide ▴
Evidence considered
- ClinVar: Uncertain significance (7 submitters).
- No expert panel or reputable source classifies as benign.
Sources
Not applicable · 3· recorded as not applicable Show reasons ▾Hide reasons ▴
PM5 N/ANo same-residue (Gln132) pathogenic comparator variant with a different amino acid change was identified. Automated PM5 candidate harvesting returned no candidates. Details ▾Hide ▴
Evidence considered
- Zero same-residue comparator variants with pathogenic classification found in ClinVar.
Sources
pm5_candidates
BP7 N/ANM_198159.3:c.394C>A is a missense variant (p.Gln132Lys), not a synonymous or intronic variant. BP7 applies only to synonymous variants with no predicted splice impact. Details ▾Hide ▴
No further detail was recorded.
PS5 N/APS5 is not a standard criterion in the ACMG/AMP 2015 classification framework (Richards et al., PMID:25741868). No reputable source reports this variant as pathogenic. Details ▾Hide ▴
No further detail was recorded.
Identifiers
- Gene
- MITF
- Transcript
- NM_198159.3
- Coding (HGVS c.)
- NM_198159.3:c.394C>A
- Protein (HGVS p.)
- NP_937802.1:p.(Gln132Lys)
- GRCh38
- chr3:69937861 C>A
- GRCh37
- chr3:69987012 C>A
- ClinVar
- 493364
Gene diagram
Every interpreted variant in MITF, mapped onto the exon structure of NM_198159.3. Select a row to find it on the plot.
MITFNM_198159.3
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 MITF
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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
203 / 1,613,992 alleles
AF 0.000126 · 0 homozygotes · FAF 0.000145
gnomAD v2.1
56 / 282,620 alleles
AF 0.000198 · 0 homozygotes · FAF 0.000859
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 0.00013 · 203 / 1,613,992 alleles · 0 hom · FAF 0.00015
| European (non-Finnish)194 / 1,180,002 | 0.00016 |
| Remaining individuals6 / 62,484 | 9.6e-05 |
| Ashkenazi Jewish1 / 29,606 | 3.4e-05 |
| Admixed American1 / 59,998 | 1.7e-05 |
| European (Finnish)1 / 64,048 | 1.6e-05 |
0 alternate alleles recorded in 5 other groups: Amish, East Asian, Middle Eastern, South Asian, African/African American.
gnomAD v2.1
AF 0.0002 · 56 / 282,620 alleles · 0 hom · FAF 0.00086
| European (non-Finnish)52 / 129,006 | 0.0004 |
| Remaining individuals2 / 7,224 | 0.00028 |
| Ashkenazi Jewish1 / 10,358 | 9.7e-05 |
| European (Finnish)1 / 25,118 | 4e-05 |
0 alternate alleles recorded in 4 other groups: African/African American, Admixed American, East Asian, South Asian.
gnomAD-Canada
AF not recorded · ? / ? alleles
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 0.000125775; MAF= 0.01258%, 203/1613992 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.000164407; MAF= 0.01644%, 194/1180002 alleles, homozygotes = 0); grpmax FAF= 0.0001452.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.000198146; MAF= 0.01981%, 56/282620 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.000403082; MAF= 0.04031%, 52/129006 alleles, homozygotes = 0); grpmax FAF= 0.0008586.
gnomAD-Canada
This variant is present in gnomAD-Canada v1.0 (AF= 0.00016290182450043442, 3/18416 alleles, homozygotes = 0).
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.260
- BayesDel
- -0.072
How the predictions were used
BP4 SupportingMultiple in silico tools predict a benign effect for p.Gln132Lys. REVEL score is 0.26 (benign, well below 0.5 pathogenic threshold), BayesDel score is -0.0715 (benign), and SpliceAI predicts no splicing impact (max delta=0.05). All three independent computational predictors are concordant for a benign interpretation. Details ▾Hide ▴
Evidence considered
- REVEL: 0.26 (benign)
- BayesDel: -0.0715 (benign)
- SpliceAI max delta: 0.05 (no predicted splicing alteration)
Sources
PP3 In silico tools do not support a deleterious effect. REVEL score is 0.26 (below the 0.5 threshold for pathogenicity), BayesDel score is -0.0715 (benign range), and SpliceAI predicts no splicing impact (max delta=0.05). All computational predictors favor a benign interpretation. Details ▾Hide ▴
Evidence considered
- REVEL: 0.26 (benign
- below 0.5 pathogenic threshold)
- BayesDel: -0.0715 (benign)
- SpliceAI max delta: 0.05 (no predicted splicing impact)
Sources
BP7 N/ANM_198159.3:c.394C>A is a missense variant (p.Gln132Lys), not a synonymous or intronic variant. BP7 applies only to synonymous variants with no predicted splice impact. Details ▾Hide ▴
No further detail was recorded.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.05). REVEL score = 0.26. BayesDel score = -0.0715447.
2 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.
Recorded publications
-
PMID 24033266 ↗A systematic approach to assessing the clinical significance of genetic variants.Duzkale H et al. · 2013Describes a variant assessment tool (VAT) methodology for systematic evaluation of genetic variants. This is a methodological paper that does not discuss the MITF c.394C>A variant.Does not name this variant
Quoted passage
To supplement these guidelines and capture the evolving state of the field, we developed a variant assessment tool (VAT) that systematically evaluates multiple lines of evidence.
-
PMID 25741868 ↗Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.Richards S et al. · 2015ACMG/AMP standards and guidelines for the interpretation of sequence variants. This foundational document defines the variant classification framework but does not discuss the MITF c.394C>A variant.Does not name this variant
Quoted passage
This report describes updated standards and guidelines for classification of sequence variants using criteria informed by expert opinion and empirical data.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
203 / 1,613,992 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.050
Open source ↗
ClinVar
7 Uncertain significance
Open source ↗
COSMIC
Captured COSMIC source record
Open source ↗
Cancer hotspots
Captured Cancer Hotspots source record
Open source ↗
OncoKB
Captured OncoKB source record
Open source ↗
All source links
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/variation/493364/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/3-69987012-C-A?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr3-69937861-C-A?dataset=gnomad_r4
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/3-69937861-C-A
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_198159.3%3Ac.394C…
- OncoKB ↗www.oncokb.org/gene/MITF/Q132K
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=MITF+c.394C%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= 0.000125775; MAF= 0.01258%, 203/1613992 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.000164407; MAF= 0.01644%, 194/1180002 alleles, homozygotes = 0); grpmax FAF= 0.0001452.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.000198146; MAF= 0.01981%, 56/282620 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.000403082; MAF= 0.04031%, 52/129006 alleles, homozygotes = 0); grpmax FAF= 0.0008586.
gnomAD-Canada
This variant is present in gnomAD-Canada v1.0 (AF= 0.00016290182450043442, 3/18416 alleles, homozygotes = 0).
ClinVar
This variant has been reported in ClinVar as Uncertain significance (7 clinical laboratories). (ClinVarID = 493364)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.05). REVEL score = 0.26. BayesDel score = -0.0715447.
Functional
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. MITF, a transcription factor involved in melanocyte differentiation, is altered by mutation and amplification in melanomas.
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.