Classification rationale

BS1BP7 Likely Benign

NF1 c.369C>G

The NF1 c.369C>G (p.Thr123=) variant has been reported in ClinVar, where benign and likely benign classifications predominate.¹ This variant is present in population databases at high frequency, including East Asian allele frequencies of 1.11791% in gnomAD v2.1 and 1.22098% in gnomAD v4.1, supporting BS1 and arguing against rarity-based pathogenic criteria.² This synonymous variant is predicted to have no significant splice impact by SpliceAI, with a maximum delta score of 0.00, supporting BP7 and not supporting PP3.³

BS1 + BP7 → Likely Benign

1 clinvar ↗

2 gnomad_v2 ↗gnomad_v4 ↗

3 spliceai ↗

Gene diagram · NM_000267.3 · variants mapped to exon structure

NF1 NM_000267.3

Fetching transcript structure from UCSC…

Applied criteria · 2 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 · supports benign

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 0.000368619; MAF= 0.03686%, 595/1614134 alleles, homozygotes = 8) and has highest observed frequency in the East Asian population (AF= 0.0122098; MAF= 1.22098%, 548/44882 alleles, homozygotes = 7); grpmax FAF= 0.0113641.

v2.1

This variant is present in gnomAD v2.1 (AF= 0.000820623; MAF= 0.08206%, 232/282712 alleles, homozygotes = 3) and has highest observed frequency in the East Asian population (AF= 0.0111791; MAF= 1.11791%, 223/19948 alleles, homozygotes = 3); grpmax FAF= 0.00989917.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.037% · 595 / 1,614,134
8 hom · FAF 1.1%

East Asian 548 / 44,882	1.2% 7 hom
Remaining individuals 26 / 62,508	0.042% 1 hom
South Asian 18 / 91,082	0.02%
Admixed American 1 / 60,012	0.0017%
European (non-Finnish) 2 / 1,180,016	0.00017%

+ 5 not observed (European (Finnish), Amish, Middle Eastern, Ashkenazi Jewish, African/African American)

gnomAD v2.1

0.082% · 232 / 282,712
3 hom · FAF 0.99%

East Asian 223 / 19,948	1.1% 3 hom
Remaining individuals 5 / 7,212	0.069%
South Asian 4 / 30,614	0.013%

+ 5 not observed (African/African American, Admixed American, Ashkenazi Jewish, European (Finnish), European (non-Finnish))

gnomAD v4 ↗ gnomAD v2 ↗

ClinVar

This variant has been reported in ClinVar as Benign (13 clinical laboratories) and as Likely benign (4 clinical laboratories). (ClinVarID = 184262)

ClinVar ↗

In silico

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

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; COSV62214161, n = 1 times).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Sources & reference links

8Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB

COSMIC

Cancer hotspots