Classification rationale

PM2 VUS

SF3B1 c.1876A>G

The SF3B1 c.1876A>G (p.Asn626Asp; p.N626D) variant has been curated as a somatic cancer variant in OncoKB and has not been reported in ClinVar.¹ This variant is rare in population databases, with gnomAD v2.1 showing 1/251158 alleles (0.00040%) and gnomAD v4.1 showing 8/1613994 alleles (0.00050%; grpmax FAF 0.000124%), which is below the 0.1% PM2 threshold.² In silico results are mixed: SpliceAI predicts no significant splice impact (maximum delta score 0.08), while REVEL is 0.60 and BayesDel is -0.0733292, so computational evidence does not independently support PP3 or BP4.³

PM2 → VUS

1 oncokb ↗clinvar ↗

2 gnomad_v2 ↗gnomad_v4 ↗

3 spliceai ↗revelbayesdel

Gene diagram · NM_012433.2 · variants mapped to exon structure

SF3B1 NM_012433.2

Fetching transcript structure from UCSC…

Applied criteria · 1 met · select any tile

Met

Not met

Not assessed

N/A

Strength very strong supporting

Pathogenic evidence

PVS

PS

PM

PP

Benign evidence

BA

BS

BP

—

Rationale

Select a criterion.

Sources

Evidence used

Gaps remaining

Rule

—

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 4.95665e-06; MAF= 0.00050%, 8/1613994 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 3.20092e-05; MAF= 0.00320%, 2/62482 alleles, homozygotes = 0); grpmax FAF= 1.24e-06.

v2.1

This variant is present in gnomAD v2.1 (AF= 3.98156e-06; MAF= 0.00040%, 1/251158 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 2.89385e-05; MAF= 0.00289%, 1/34556 alleles, homozygotes = 0).

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.0005% · 8 / 1,613,994
0 hom · FAF 0.00012%

Remaining individuals 2 / 62,482	0.0032%
Admixed American 1 / 60,000	0.0017%
European (non-Finnish) 5 / 1,179,978	0.00042%

+ 7 not observed (European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)

gnomAD v2.1

0.0004% · 1 / 251,158
0 hom

Admixed American

1 / 34,556

0.0029%

+ 7 not observed (African/African American, Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), Remaining individuals, South Asian)

gnomAD v4 ↗ gnomAD v2 ↗

ClinVar

This variant is absent from ClinVar.

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.08). REVEL score = 0.6. BayesDel score = -0.0733292.

SpliceAI ↗

Functional Likely Oncogenic

OncoKB identified variant-specific curated literature and context relevant to functional review; curated oncogenicity label: Likely Oncogenic.

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

This variant lies in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV59206442, n = 12 times).

Hotspots

This variant lies in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Sources & reference links

7Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB

COSMIC

Cancer hotspots