Classification rationale

BA1BS2BP4BP6BP7 Benign

MBD4 c.1543+14C>T

NM_001276270.2:c.1543+14C>T is an intronic variant in MBD4 with an allele frequency of 19.55% in gnomAD v2.1 (55,283/282,782 alleles, 8,420 homozygotes), far exceeding the BA1 stand-alone benign threshold.¹ The variant is present in homozygous state in 8,420 individuals in gnomAD v2.1 and 26,307 in gnomAD v4.1, meeting BS2 at strong benign strength, inconsistent with a pathogenic role in MBD4-associated disease.² SpliceAI predicts no splicing impact (max delta score = 0.00) for this +14 intronic variant, consistent with BP4 and BP7 at supporting benign strength.³ ClinVar reports this variant as Benign by 3 clinical laboratories (variation ID 1236364), meeting BP6 at supporting benign strength.⁴

BA1 + BS2 + BP4 + BP6 + BP7 → Benign

1 gnomad_v2 ↗gnomad_v4 ↗

2 gnomad_v2 ↗gnomad_v4 ↗

3 spliceai ↗

4 clinvar ↗

Gene diagram · NM_001276270.2 · variants mapped to exon structure

MBD4 NM_001276270.2

Fetching transcript structure from UCSC…

Applied criteria · 5 applied · 13 assessed

Applied · 5

Strength Supporting Moderate Strong Very strong

✓

BA1 stand-alone Benign

Allele frequency of 19.55% in gnomAD v2.1 (55,283/282,782 alleles) and 14.50% in gnomAD v4.1 (233,804/1,612,992 alleles) far exceeds the BA1 threshold of >1% for generic ACMG. Highest subpopulation frequency is 48.47% in East Asian (gnomAD v2.1). The variant is observed in 8,420 homozygous individuals in v2.1 and 26,307 in v4.1.

gnomAD v2.1: total AF=19.55% (55283/282782 alleles

gnomad_v2 ↗gnomad_v4 ↗

✓

BS2 strong Benign

Observed in 8,420 homozygous individuals in gnomAD v2.1 and 26,307 in v4.1, with no reported severe disease phenotype. Homozygous observation in a gene where germline LoF is associated with an autosomal dominant/recessive cancer predisposition syndrome strongly supports a benign interpretation.

8420 homozygotes in gnomAD v2.1.26

gnomad_v2 ↗gnomad_v4 ↗

✓

BP4 supporting Benign

SpliceAI predicts no splicing impact (max delta score = 0.00). REVEL and BayesDel scores are not available for this intronic variant, but the absence of any predicted splicing alteration supports a benign interpretation.

SpliceAI: max delta = 0.00no predicted acceptor gain/loss or donor gain/loss.REVEL and BayesDel not available for intronic variants.

spliceai ↗

✓

BP6 supporting Benign

ClinVar reports this variant as Benign by 3 clinical laboratories (GeneDx, ARUP Laboratories, Labcorp Genetics). Although the review status is 1-star (criteria provided, single submitter), three independent clinical laboratories agree on a benign classification, which constitutes a reputable source under generic ACMG BP6.

ClinVar variation ID 1236364: Benign classification.3 clinical laboratories: GeneDxARUP Laboratories

clinvar ↗

✓

BP7 supporting Benign

This is an intronic variant at position +14 from the exon 6 donor site with SpliceAI delta score of 0.00, indicating no predicted impact on splicing. BP7 applies to synonymous and intronic variants where splicing prediction algorithms predict no impact on the splice consensus sequence.

Intronic variant at c.1543+14 (14 bases downstream of exon 6).SpliceAI max delta = 0.00no predicted alteration of splicing.

spliceai ↗

Assessed · not applied

Pathogenic

PS2 No de novo observation reported for this variant in the available case materials.

PS3 No functional data exists for this intronic variant.

PS4 Variant is extremely common in population databases (gnomAD AF ~19.5%), precluding a statistically increased prevalence in affected individuals for any rare disease.

PM2 Variant is present at very high frequency in gnomAD (v2.1 AF=19.55%, v4.1 AF=14.50%), far exceeding the PM2 threshold of <0.1%.

PM6 No de novo observation reported for this variant.

PP1 No co-segregation data available.

PP3 SpliceAI predicts no splice impact (max delta score = 0.00).

PP4 Variant is present in ~19.5% of the general population, which is incompatible with a variant causing a rare disease with high specificity.

PP5 ClinVar reports this variant as Benign, not Pathogenic.

Benign

BS3 No functional studies demonstrating no deleterious effect for this variant are available.

BS4 No segregation data available.

BP2 No observation of this variant in trans with a known pathogenic variant is reported in the case materials.

BP5 No alternate molecular basis for disease has been identified in cases with this variant in the available materials.

N/A · 7 PVS1 · PS1 · PM1 · PM5 · PP2 · BS1 · BP1

Research & evidence

Population frequency · supports benign

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 0.144951; MAF= 14.49505%, 233804/1612992 alleles, homozygotes = 26307) and has highest observed frequency in the African/African American population (AF= 0.47474; MAF= 47.47397%, 35558/74900 alleles, homozygotes = 8500); grpmax FAF= 0.470605.

v2.1

This variant is present in gnomAD v2.1 (AF= 0.195497; MAF= 19.54969%, 55283/282782 alleles, homozygotes = 8420) and has highest observed frequency in the East Asian population (AF= 0.484706; MAF= 48.47056%, 9666/19942 alleles, homozygotes = 2374); grpmax FAF= 0.476196.

🇨🇦 CA

This variant is present in gnomAD-Canada v1.0 (AF= 0.1828804347826087, 3365/18400 alleles, homozygotes = 464).

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

14% · 233804 / 1,612,992
26307 hom · FAF 47%

African/African American 35558 / 74,900	47% 8500 hom
East Asian 19716 / 44,858	44% 4415 hom
South Asian 24706 / 91,044	27% 3588 hom
Admixed American 14754 / 60,008	25% 1886 hom
Middle Eastern 1072 / 6,060	18% 115 hom
Ashkenazi Jewish 5147 / 29,586	17% 463 hom
Remaining individuals 10826 / 62,474	17% 1223 hom
Amish 96 / 908	11% 5 hom
European (non-Finnish) 119032 / 1,179,132	10% 6031 hom
European (Finnish) 2897 / 64,022	4.5% 81 hom

gnomAD v2.1

20% · 55283 / 282,782
8420 hom · FAF 48%

East Asian 9666 / 19,942	48% 2374 hom
African/African American 11883 / 24,948	48% 2831 hom
South Asian 8338 / 30,612	27% 1216 hom
Admixed American 8425 / 35,428	24% 1069 hom
Ashkenazi Jewish 1787 / 10,370	17% 153 hom
Remaining individuals 1174 / 7,224	16% 109 hom
European (non-Finnish) 12916 / 129,144	10% 641 hom
European (Finnish) 1094 / 25,114	4.4% 27 hom

gnomAD Canada 🇨🇦

18% · 3365 / 18,400
464 hom · FAF 46%

indel · split

African/African American 503 / 1,018	49% 130 hom
East Asian 645 / 1,338	48% 157 hom
South Asian 394 / 1,360	29% 49 hom
Latino/Admixed American 191 / 838	23% 18 hom
Remaining individuals 256 / 1,134	23% 30 hom
Middle Eastern 27 / 144	19%
Ashkenazi Jewish 123 / 830	15% 13 hom
European (non-Finnish) 1226 / 11,730	10% 67 hom

+ 1 not observed (European (Finnish))

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant has been reported in ClinVar as Benign (3 clinical laboratories). (ClinVarID = 1236364)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).

SpliceAI ↗

Functional No data

No calibrated functional assay or RNA evidence was identified for this variant.

OncoKB ↗

COSMIC

Somatic evidence

COSMIC

This variant has not previously been reported in somatic cancers (COSMIC).

Hotspots

This variant does not lie in a statistically significant cancer hotspot.

COSMIC ↗

Sources & reference links

7Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Triaged references · 2 PMIDs not cited in assessment

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. CLINVAR

28492532 ↗ Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. CLINVAR