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.
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.MBD4 encodes a DNA glycosylase that detects and repairs deaminated methyl-cytosines in DNA, using a methyl-CpG binding domain to anchor to methylated DNA and a glycosylase domain to carry out mismatch repair in CpG-rich regions. The protein also helps repress transcription from methylated gene promoters. MBD4 acts as a tumor suppressor, and its loss has been linked to colorectal cancer, acute myeloid leukemia, and uveal melanoma.
The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
The applied criteria and their strengths are shown as assessed under the stated framework.
No pathogenic criterion marked as applied in the recorded assessment.
Met, supporting: synonymous variant with SpliceAI max delta 0.033, below the <=0.1 no-impact threshold.
VUS: BP7 (supporting) was the only applied criterion, and one supporting benign criterion does not meet generic ACMG/AMP benign or likely benign thresholds.
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1: 185 / 1,614,060 alleles. Recorded AF 0.000114618. Recorded homozygote count 0.
This variant is present in gnomAD v2.1 (AF= 0.000201621; MAF= 0.02016%, 57/282708 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.00200337; MAF= 0.20034%, 50/24958 alleles, homozygotes = 0); grpmax FAF= 0.00148612.
Not available in gnomAD-Canada v1.0.
Recorded SpliceAI maximum delta score: 0.033. Refer to the recorded PP3/BP4 rationale for interpretation.
3 Likely benign · 2 Benign. ClinVar API review status: criteria provided, multiple submitters, no conflicts.
OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.
This variant has previously been reported in somatic cancers (COSMIC; COSV51444911, n = 1 times).
This variant does not lie in a statistically significant hotspot.
ACMG/AMP criteria under Not recorded, with the data and sources behind each one.
28 criteria with recorded statuses: 1 met · 8 not met · 11 not assessed · 8 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
No MBD4-specific VCEP or gene-specific framework was available; generic ACMG/AMP rules were therefore used.
PS4, PP4, and BP5 lack the required variant-specific clinical evidence and are not assessed.
PP5 and BP6 are not triggered because ClinVar contains no exact-variant expert-panel submission; the available Benign/Likely benign labels are ordinary laboratory submissions.
This synonymous variant is evaluated through the SpliceAI path only; REVEL and BayesDel are not applicable.
The single SpliceAI prediction has maximum delta 0.033 and is allocated to BP7 rather than reused across PP3 or BP4.
All four requested population criteria were assessed using the supplied generic thresholds because no governing MBD4-specific VCEP specification was available.
Default all-comers gnomAD totals were used; no GNOMAD_V2_1_NON_CANCER or GNOMAD_V3_1_NON_CANCER records were present in the supplied evidence.
No criteria match.
The variant is synonymous (NM_001276270.2:c.1074C>T; NP_001263199.1:p.(Ile358=)), satisfying BP7's consequence scope. The applicable SpliceAI result shows no significant predicted splice impact, with a maximum delta score of 0.033, below the supplied <=0.1 supporting cutoff. This SpliceAI prediction is used here and is not double-counted for PP3 or BP4.
No governing MBD4-specific population specification was identified, so the supplied generic PM2 threshold of allele frequency <=0.0001 was applied to default all-comers totals. The variant has AF 0.000201621 in gnomAD v2.1 and AF 0.000114618 in gnomAD v4.1, both above 0.0001; therefore PM2 is not met. Although gnomAD v4.1 exome-only AF is 0.0000779847, an exome-only source is not specified here and cannot replace the default all-comers total.
PM2 requires allele frequency <=0.0001 under the supplied generic threshold; default all-comers totals apply absent a governing exome-only or non-cancer rule.
The variant is synonymous (NM_001276270.2:c.1074C>T; NP_001263199.1:p.(Ile358=)), so the applicable computational path is SpliceAI rather than REVEL. SpliceAI is available and its maximum delta score is 0.033, below the generic PP3 supporting threshold of >=0.2 from the supplied Jaganathan et al. 2019 calibration. The same SpliceAI prediction is allocated to BP7 and is not double-counted for PP3.
PP5 is not met. The exact variant NM_001276270.2:c.1074C>T (p.Ile358=) has ClinVar submissions classified as Benign or Likely benign, but all are ordinary laboratory submissions with single-submitter review status; the record reports zero expert-panel submissions. Under the specified rule, only an exact-variant ClinVar expert-panel Pathogenic or Likely pathogenic classification can support PP5, so the available ClinVar labels cannot trigger PP5.
{'framework': 'generic ACMG/AMP with specified expert-panel restriction', 'definition': 'PP5 may be applied only when an exact-variant ClinVar expert panel classifies the variant as Pathogenic or Likely pathogenic.', 'numeric_operator': None, 'numeric_threshold': None}
No governing MBD4-specific population specification was identified, so the supplied generic ACMG/AMP BA1 threshold of allele frequency >=0.05 was applied to default all-comers gnomAD totals. The variant has AF 0.000201621 in gnomAD v2.1 (57/282708 alleles) and AF 0.000114618 in gnomAD v4.1 (185/1614060 alleles); the highest reported ancestry-specific AF is 0.00200337 in gnomAD v2.1 and 0.00198593 in gnomAD v4.1. These values are far below 0.05, so BA1 is not met.
BA1 requires allele frequency >=0.05 under the supplied generic threshold.
No governing MBD4-specific population specification was identified, so the supplied generic BS1 threshold of allele frequency >=0.01 was applied to default all-comers gnomAD totals. The variant's AF is 0.000201621 in gnomAD v2.1 and 0.000114618 in gnomAD v4.1, while the highest ancestry-specific values are 0.00200337 and 0.00198593, respectively. All observed frequencies are below 0.01, so BS1 is not met.
BS1 requires allele frequency >=0.01 under the supplied generic threshold.
The supplied population data show no homozygotes in gnomAD v2.1 (57 alternate alleles) or gnomAD v4.1 (185 alternate alleles). Because BS2 requires observation in an appropriately healthy individual in the relevant genotype context, and no qualifying homozygous or clinically phenotyped healthy observation is reported, BS2 is not met; absence of homozygotes is not itself BS2 evidence.
BS2 requires observation in a healthy individual in the applicable genotype context; zero homozygotes does not satisfy BS2.
The variant is synonymous, so BP4 would use the SpliceAI path; REVEL and BayesDel are not applicable. SpliceAI maximum delta is 0.033, which is below the supplied BP4 supporting threshold of <=0.1. However, this same prediction is used for BP7, the synonymous-specific criterion, and cannot be double-counted as independent BP4 evidence. No separate computational prediction is available to support BP4 after this allocation.
BP6 is not met. The exact variant NM_001276270.2:c.1074C>T (p.Ile358=) has ClinVar submissions classified as Benign or Likely benign, but all are ordinary laboratory submissions with single-submitter review status; the record reports zero expert-panel submissions. Under the specified rule, only an exact-variant ClinVar expert-panel Benign or Likely benign classification can support BP6, so ordinary laboratory submissions and aggregate labels cannot trigger BP6.
{'framework': 'generic ACMG/AMP with specified expert-panel restriction', 'definition': 'BP6 may be applied only when an exact-variant ClinVar expert panel classifies the variant as Benign or Likely benign.', 'numeric_operator': None, 'numeric_threshold': None}
No documented de novo observation is available for NM_001276270.2:c.1074C>T (MBD4), including confirmed variant presence in the proband and confirmed absence in both biological parents. The available case materials contain no parental genotypes, trio testing, maternity/paternity confirmation, or phenotype-linked de novo case report. Therefore PS2 cannot be assessed.
No variant-specific functional study was identified for NM_001276270.2:c.1074C>T (MBD4; p.Ile358=). The available literature consists of general ACMG/AMP guidance or papers unrelated to this variant and contains no validated assay measuring MBD4 function, no disease-relevant experimental system, and no assay controls supporting a loss-of-function effect. Therefore PS3 cannot be applied at any strength.
No applicable MBD4-specific VCEP framework was available, so the generic ACMG/AMP framework applies. PS4 requires the variant to be observed in affected individuals at a significantly increased frequency compared with controls. The available case evidence contains no variant-specific case series, case-control comparison, odds ratio, enrichment statistic, or affected-case count for NM_001276270.2:c.1074C>T (p.Ile358=).
{'framework': 'generic ACMG/AMP', 'definition': 'PS4 requires the variant to be observed in affected individuals at a significantly increased frequency compared with controls.', 'numeric_operator': None, 'numeric_threshold': None}
No MBD4-specific VCEP or gene framework was available, so generic ACMG/AMP PM3 was considered. The case evidence does not document an affected proband with this variant, a second pathogenic MBD4 variant, confirmed biallelic inheritance, or phase showing this variant in trans with a pathogenic allele. The available variant record identifies NM_001276270.2:c.1074C>T as synonymous (p.Ile358=) but provides no segregation or phase observations. PM3 therefore cannot be assessed from the available evidence.
Generic ACMG/AMP PM3: supporting evidence requires the variant to be observed in trans with a pathogenic variant in an affected individual with a recessive disorder; phase and relevant phenotype must be established.
No suspected de novo occurrence without parental testing is documented for NM_001276270.2:c.1074C>T (MBD4). The available materials do not identify a proband case with a compatible phenotype, nor do they provide family history, parental genotypes, or a clinical report supporting presumed de novo status. Therefore PM6 cannot be assessed.
No affected relatives carrying NM_001276270.2:c.1074C>T are documented, and no segregation series, informative meioses, pedigree, or quantitative segregation analysis is available. Phenotype consistency among variant-positive relatives therefore cannot be evaluated, so PP1 cannot be assessed.
No applicable MBD4-specific VCEP framework was available, so the generic ACMG/AMP framework applies. PP4 requires the patient's phenotype or family history to be highly specific for a disease with a single genetic etiology. The available evidence does not provide a patient phenotype, family history, diagnostic phenotype match, or disease-specific clinical description linked to this exact variant.
{'framework': 'generic ACMG/AMP', 'definition': "PP4 requires the patient's phenotype or family history to be highly specific for a disease with a single genetic etiology.", 'numeric_operator': None, 'numeric_threshold': None}
No variant-specific functional study was identified for NM_001276270.2:c.1074C>T (MBD4; p.Ile358=). The available literature contains no validated disease-relevant assay demonstrating normal MBD4 function for this allele, no quantitative benign-effect threshold, and no adequate assay controls from which BS3 strength could be calibrated. Therefore BS3 cannot be applied at any strength.
No unaffected relatives who were tested and found to carry NM_001276270.2:c.1074C>T are documented, and no phenotype-appropriate family with reliable clinical assessment is available. Consequently, absence of segregation cannot be evaluated and BS4 cannot be assessed.
No MBD4-specific VCEP or gene framework was available, so generic ACMG/AMP BP2 was considered. The case evidence does not document this variant in cis with a pathogenic variant or in trans with a benign variant in an affected individual, nor does it provide phase, affected-proband, or inheritance data needed to establish either BP2 scenario. The available variant record identifies NM_001276270.2:c.1074C>T as synonymous (p.Ile358=), but that consequence and the reported population observations do not establish an allelic BP2 relationship. BP2 therefore cannot be assessed from the available evidence.
Generic ACMG/AMP BP2: supporting evidence requires the variant to be observed in cis with a pathogenic variant or in trans with a benign variant in an affected individual, with phase established.
No applicable MBD4-specific VCEP framework was available, so the generic ACMG/AMP framework applies. BP5 requires the variant to be found in a case with an alternate molecular basis for the disease. The available evidence contains no affected-case report for this exact variant and no confirmed alternate molecular diagnosis or molecular basis that could satisfy BP5. No BP5-specific numeric likelihood-ratio threshold is available in the governing generic framework, so no threshold comparison can be performed.
{'framework': 'generic ACMG/AMP', 'definition': 'BP5 requires the variant to be found in a case with an alternate molecular basis for the disease.', 'numeric_operator': None, 'numeric_threshold': None}
deterministic_prefilter: requires_null_variant_class
deterministic_prefilter: requires_missense
deterministic_prefilter: requires_missense
deterministic_prefilter: requires_stop_loss_or_nonrepeat_indel
deterministic_prefilter: requires_missense
deterministic_prefilter: requires_missense
deterministic_prefilter: requires_missense
deterministic_prefilter: requires_repeat_region_indel
Every interpreted variant in MBD4, mapped onto the exon structure of NM_001276270.2. Select a row to find it on the plot.
| Protein | Location | Classification | Link |
|---|
| African/African American149 / 75,028 | 0.002 |
| Middle Eastern1 / 6,062 | 0.00016 |
| Remaining individuals4 / 62,508 | 6.4e-05 |
| European (non-Finnish)29 / 1,180,006 | 2.5e-05 |
| East Asian1 / 44,870 | 2.2e-05 |
| Admixed American1 / 60,018 | 1.7e-05 |
| African/African American50 / 24,958 | 0.002 |
| Remaining individuals1 / 7,216 | 0.00014 |
| European (non-Finnish)6 / 129,066 | 4.6e-05 |
This variant is present in gnomAD v4.1 (AF= 0.000114618; MAF= 0.01146%, 185/1614060 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.00198593; MAF= 0.19859%, 149/75028 alleles, homozygotes = 0); grpmax FAF= 0.00172518.
This variant is present in gnomAD v2.1 (AF= 0.000201621; MAF= 0.02016%, 57/282708 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.00200337; MAF= 0.20034%, 50/24958 alleles, homozygotes = 0); grpmax FAF= 0.00148612.
Not available in gnomAD-Canada v1.0.
The variant is synonymous (NM_001276270.2:c.1074C>T; NP_001263199.1:p.(Ile358=)), satisfying BP7's consequence scope. The applicable SpliceAI result shows no significant predicted splice impact, with a maximum delta score of 0.033, below the supplied <=0.1 supporting cutoff. This SpliceAI prediction is used here and is not double-counted for PP3 or BP4.
The variant is synonymous (NM_001276270.2:c.1074C>T; NP_001263199.1:p.(Ile358=)), so the applicable computational path is SpliceAI rather than REVEL. SpliceAI is available and its maximum delta score is 0.033, below the generic PP3 supporting threshold of >=0.2 from the supplied Jaganathan et al. 2019 calibration. The same SpliceAI prediction is allocated to BP7 and is not double-counted for PP3.
The variant is synonymous, so BP4 would use the SpliceAI path; REVEL and BayesDel are not applicable. SpliceAI maximum delta is 0.033, which is below the supplied BP4 supporting threshold of <=0.1. However, this same prediction is used for BP7, the synonymous-specific criterion, and cannot be double-counted as independent BP4 evidence. No separate computational prediction is available to support BP4 after this allocation.
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03).
7 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.
The variant classification approach described in this paper is meant to be applicable to variants in all Mendelian genes whether identified by single gene tests, multi-gene panels, exome sequencing or genome sequencing.
Proposed Criteria for Interpretation of Sequence Variants, paragraph 2
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
This variant is present in gnomAD v4.1 (AF= 0.000114618; MAF= 0.01146%, 185/1614060 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.00198593; MAF= 0.19859%, 149/75028 alleles, homozygotes = 0); grpmax FAF= 0.00172518.
This variant is present in gnomAD v2.1 (AF= 0.000201621; MAF= 0.02016%, 57/282708 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.00200337; MAF= 0.20034%, 50/24958 alleles, homozygotes = 0); grpmax FAF= 0.00148612.
Not available in gnomAD-Canada v1.0.
This variant has been reported in ClinVar as Likely benign (3 clinical laboratories) and as Benign (2 clinical laboratories). (ClinVarID = 2045455)
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03).
OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV51444911, n = 1 times).
This variant does not lie in a statistically significant hotspot.