Classification rationale

VUS

NF1 c.2747A>G

The NF1 c.2747A>G (p.Asn916Ser) variant has been reported in ClinVar with conflicting germline classifications, including uncertain significance and likely benign, and without an expert panel assertion.¹ This variant is present at low frequency in population databases: gnomAD v4.1 shows an allele frequency of 0.00570% (92/1613808 alleles; grpmax FAF 0.006229%) and gnomAD v2.1 shows an allele frequency of 0.00239% (6/251122 alleles), which is below benign frequency thresholds but means the variant is not absent from controls.² SpliceAI predicts no significant splice impact for this variant, with a maximum delta score of 0.01, so in silico splicing evidence does not independently support pathogenicity.³

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 · 0 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= 5.7008e-05; MAF= 0.00570%, 92/1613808 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 7.54351e-05; MAF= 0.00754%, 89/1179822 alleles, homozygotes = 0); grpmax FAF= 6.229e-05.

v2.1

This variant is present in gnomAD v2.1 (AF= 2.38928e-05; MAF= 0.00239%, 6/251122 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 5.2897e-05; MAF= 0.00529%, 6/113428 alleles, homozygotes = 0); grpmax FAF= 2.298e-05.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.0057% · 92 / 1,613,808
0 hom · FAF 0.0062%

European (non-Finnish) 89 / 1,179,822	0.0075%
Remaining individuals 2 / 62,470	0.0032%
African/African American 1 / 74,918	0.0013%

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

gnomAD v2.1

0.0024% · 6 / 251,122
0 hom · FAF 0.0023%

European (non-Finnish)

6 / 113,428

0.0053%

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

gnomAD v4 ↗ gnomAD v2 ↗

ClinVar

This variant has been reported in ClinVar as Uncertain significance (6 clinical laboratories) and as Likely benign (2 clinical laboratories).

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).

SpliceAI ↗

Functional Unknown Oncogenic Effect

OncoKB has not reviewed this specific variant; no variant-level oncogenicity or biological effect is available. Gene-level context: NF1, a negative regulator of RAS, is inactivated by mutation or deletion in various solid and hematologic malignancies.

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; COSV62223654, 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