Classification rationale

BP7 VUS

MBD4 c.1074C>T synonymous · exon 3

BP7 supporting: synonymous variant with SpliceAI max delta 0.033, below the <=0.1 no-impact threshold.

BP7 → VUS

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.

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

MBD4 NM_001276270.2

Fetching transcript structure from UCSC…

Applied criteria · 1 applied · 19 assessed

MetEvidence satisfies this criterion.

Not metEvaluated against available evidence; threshold not reached.

Not assessedApplies in principle, but no evidence was found to evaluate it.

N/ADoesn't apply to this variant type.

Applied · 1

Strength Supporting Moderate Strong Very strong

BP7 supporting Benign

Met, supporting: synonymous variant with SpliceAI max delta 0.033, below the <=0.1 no-impact threshold.

The normalized consequence is synonymous: NM_001276270.2:c.1074C>T produces NP_001263199.1:p.(Ile358=).SpliceAI reports DS_AG 0.001, DS_AL 0.033, DS_DG 0.0, and DS_DL 0.007; maximum delta = 0.033.The supplied generic SpliceAI calibration defines a no-significant-impact BP4 cutoff of <=0.1 (Jaganathan et al. 2019, PMID:30661751), applied here as the calibrated splice-impact basis for BP7.

spliceai ↗

Assessed · not applied · 8 not met · 11 not assessed

Pathogenic

PS2 Not assessed: no documented proband genotype with confirmed absence of NM_001276270.2:c.1074C>T in both biological parents.

PS3 Not assessed: no variant-specific validated functional assay with appropriate controls is reported for synonymous MBD4 c.1074C>T (p.Ile358=).

PS4 Not assessed: no variant-specific affected-case count, control comparison, or enrichment statistic is available for PS4.

PM2 Not met: gnomAD v4.1 all-comers AF 0.000114618 exceeds the supplied PM2 threshold of 0.0001.

PM3 Not assessed: no affected proband, second pathogenic MBD4 allele, or confirmed trans phase is documented for this synonymous variant.

PM6 Not assessed: no compatible proband case or presumed de novo occurrence without parental testing is documented for this variant.

PP1 Not assessed: no affected variant-positive relatives, informative meioses, or segregation series are documented for this variant.

PP3 Not met: synonymous-variant SpliceAI max delta 0.033 is below the >=0.2 PP3 supporting threshold.

PP4 Not assessed: no patient phenotype, family history, or disease-specific clinical match is available for this exact variant.

PP5 Not met: ClinVar has zero expert-panel submissions, and its exact-variant laboratory classifications are Benign or Likely benign.

Benign

BA1 Not met: gnomAD v4.1 all-comers AF 0.000114618 is far below the supplied BA1 threshold of 0.05.

BS1 Not met: the highest observed gnomAD ancestry-specific AF is 0.00200337, below the supplied BS1 threshold of 0.01.

BS2 Not met: gnomAD reports zero homozygotes, with no qualifying healthy individual observed in the genotype context required for BS2.

BS3 Not assessed: no controlled variant-specific assay demonstrates normal MBD4 function for c.1074C>T (p.Ile358=) or provides a benign-effect threshold.

BS4 Not assessed: no clinically evaluated unaffected relatives with confirmed variant carriage are documented for this variant.

BP2 Not assessed: no affected individual has documented cis or trans phase with a pathogenic or benign MBD4 allele for this variant.

BP4 Not met: SpliceAI max delta 0.033 meets <=0.1, but the same prediction is allocated to BP7 and cannot be double-counted for BP4.

BP5 Not assessed: no affected case with a confirmed alternate molecular basis is documented for this exact variant.

BP6 Not met: ClinVar has zero expert-panel submissions, so its exact-variant laboratory Benign or Likely benign labels cannot trigger BP6.

N/A · 8 PVS1 · PS1 · PM1 · PM4 · PM5 · PP2 · BP1 · BP3

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

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.

v2.1

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.

🇨🇦 CA

Not available in gnomAD-Canada v1.0.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.011% · 185 / 1,614,060
0 hom · FAF 0.17%

African/African American 149 / 75,028	0.2%
Middle Eastern 1 / 6,062	0.016%
Remaining individuals 4 / 62,508	0.0064%
European (non-Finnish) 29 / 1,180,006	0.0025%
East Asian 1 / 44,870	0.0022%
Admixed American 1 / 60,018	0.0017%

+ 4 not observed (European (Finnish), Amish, South Asian, Ashkenazi Jewish)

gnomAD v2.1

0.02% · 57 / 282,708
0 hom · FAF 0.15%

African/African American 50 / 24,958	0.2%
Remaining individuals 1 / 7,216	0.014%
European (non-Finnish) 6 / 129,066	0.0046%

+ 5 not observed (Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), South Asian)

gnomAD Canada 🇨🇦

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant has been reported in ClinVar as Likely benign (3 clinical laboratories) and as Benign (2 clinical laboratories). (ClinVarID = 2045455)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03).

SpliceAI ↗

Functional Unknown Oncogenic Effect

OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV51444911, n = 1 times).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Sources & reference links

8Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Cancer hotspots

Triaged references · 7 PMIDs not cited in assessment

23619275 ↗ ACMG position statement on prenatal/preconception expanded carrier screening. CLINVAR

25730230 ↗ Expanded carrier screening in reproductive medicine-points to consider: a joint statement of the American College of Medical Genetics and Genomics, American College of Obstetricians and Gynecologists, National Society of Genetic Counselors, Perinatal Quality Foundation, and Society for Maternal-Fetal Medicine. CLINVAR

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

23037933 ↗ Including the initial newborn screening bloodspot collection device serial number on birth certificates: basis and recommendations from the Secretary of Health and Human Services' Advisory Committee on Heritable Disorders in Newborns and Children. CLINVAR

24022298 ↗ Offering prenatal diagnostic tests: European guidelines for clinical practice [corrected]. CLINVAR

24394680 ↗ Parental permission for pilot newborn screening research: guidelines from the NBSTRN. CLINVAR

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

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