Applied · 6

Strength Supporting Moderate Strong Very strong

✓

BA1 stand-alone Benign

The allele frequency in the African/African American population exceeds 1%: gnomAD v2.1 AF=4.80% (1199/24,960 alleles, 31 homozygotes, grpmax FAF=4.58%); gnomAD v4.1 AF=4.90% (3673/75,010 alleles, 86 homozygotes, grpmax FAF=4.76%). The overall population AF is 0.47% (v2.1) and 0.27% (v4.1). The African subpopulation frequency far exceeds the BA1 threshold of >1% and is incompatible with a highly penetrant Mendelian disorder.

gnomAD v2.1 African/African American AF=4.80%31 homozygotesgrpmax FAF=4.58%

gnomad_v2 ↗gnomad_v4 ↗

✓

BS1 strong Benign

The allele frequency in the African/African American population exceeds 0.3%: gnomAD v2.1 AF=4.80%; gnomAD v4.1 AF=4.90%. The overall global AF is also elevated at 0.47% (v2.1). This is substantially above the BS1 threshold of >0.3% for a dominant disorder with high penetrance.

gnomAD v2.1 overall AF=0.47% (>0.3% BS1 threshold)gnomAD v4.1 African AF=4.90% (>>0.3% BS1 threshold)Overall and subpopulation frequencies both exceed BS1 threshold

gnomad_v2 ↗gnomad_v4 ↗

✓

BS2 strong Benign

This variant has been observed in the homozygous state in 32 healthy individuals in gnomAD v2.1 and 89 healthy individuals in gnomAD v4.1. Observation in the homozygous state in population databases demonstrates that this variant does not cause a highly penetrant dominant or recessive disease in these individuals.

gnomAD v2.1: 32 homozygotesgnomAD v4.1: 89 homozygotesHomozygous state incompatible with highly penetrant dominant disease

gnomad_v2 ↗gnomad_v4 ↗

✓

BP4 supporting Benign

Multiple lines of computational evidence support a benign effect. SpliceAI predicts no significant splice impact (max delta score 0.01). REVEL and BayesDel scores are not available as this is a synonymous variant without missense consequence. The synonymous nature itself, combined with no predicted splice alteration, supports a benign interpretation.

SpliceAI max delta: 0.01 — no predicted splice impactSynonymous change — no amino acid alterationNo computational tool predicts deleterious effect

spliceai ↗

✓

BP6 supporting Benign

ClinVar classifies NM_006445.3:c.6247C>T as Benign (VariationID 321876; review status: criteria provided, single submitter). Three independent clinical laboratories concur on a benign classification, providing supporting evidence for a benign interpretation.

ClinVar classification: Benign by 3 clinical laboratoriesVariationID 321876

clinvar ↗

✓

BP7 supporting Benign

NM_006445.3:c.6247C>T is a synonymous variant (p.Leu2083=) with SpliceAI predicting no significant splice impact (max delta score 0.01). No new splice site creation or disruption of the consensus splice site is predicted. The variant does not affect the encoded amino acid sequence.

Synonymous variant (p.Leu2083=) — no amino acid changeSpliceAI max delta: 0.01 — no predicted splice impactMutalyzer confirms synonymous consequence

spliceai ↗

Assessed · not applied

Pathogenic

PS2 PS2 requires a confirmed de novo observation (both maternity and paternity confirmed) in a patient with disease and no family history.

PS3 PS3 requires well-established in vitro or in vivo functional studies demonstrating a damaging effect.

PS4 PS4 requires the prevalence of the variant in affected individuals to be significantly increased compared to controls.

PM1 PM1 requires the variant to be located in a mutational hotspot or critical, well-established functional domain without benign variation.

PM2 PM2 requires absence from (or very low frequency in) population databases (<0.1% for non-VCEP).

PM6 PM6 requires a de novo observation without confirmation of paternity and maternity.

PP1 PP1 requires cosegregation with disease in multiple affected family members.

PP3 PP3 requires multiple lines of computational evidence supporting a deleterious effect.

PP4 PP4 requires the patient's phenotype or family history to be highly specific for the gene.

PP5 PP5 requires a reputable source to have recently classified this variant as pathogenic.

Benign

BS3 BS3 requires well-established in vitro or in vivo functional studies showing no damaging effect.

BS4 BS4 requires lack of segregation with disease in affected family members.

BP2 BP2 requires the variant to be observed in trans with a known pathogenic variant in a gene associated with a fully penetrant dominant disorder, OR observed in cis with a pathogenic variant in any inheritance pattern.

BP5 BP5 requires an alternate molecular basis for disease to have been identified in the patient.

N/A · 5 PVS1 · PS1 · PM5 · PP2 · BP1

African/African American 3673 / 75,010	4.9% 86 hom
Middle Eastern 21 / 6,062	0.35%
Admixed American 197 / 60,008	0.33%
Remaining individuals 201 / 62,510	0.32% 2 hom
South Asian 24 / 91,082	0.026% 1 hom
European (non-Finnish) 192 / 1,180,036	0.016%
East Asian 1 / 44,878	0.0022%

African/African American 1199 / 24,960	4.8% 31 hom
Admixed American 88 / 35,440	0.25%
Remaining individuals 11 / 7,228	0.15%
South Asian 9 / 30,616	0.029% 1 hom
European (non-Finnish) 20 / 129,192	0.015%

African/African American 41 / 1,020	4%
Middle Eastern 1 / 144	0.69%
Latino/Admixed American 4 / 838	0.48%
Remaining individuals 3 / 1,138	0.26%
European (non-Finnish) 6 / 11,738	0.051%