Classification rationale

BP7 VUS

NF1 c.4686A>G

The NF1 c.4686A>G (p.Glu1562=) variant has been reported in ClinVar predominantly as likely benign or benign, with some uncertain significance submissions.¹ This variant is present in population databases, including gnomAD v2.1 at an allele frequency of 0.000226663 (64/282358) and gnomAD v4.1 at an allele frequency of 0.000223144, which is below common benign strong thresholds but inconsistent with absence from controls.² In silico splice prediction does not support a splice-disrupting effect, with SpliceAI showing a maximum delta score of 0.01.³

BP7 → VUS

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 · 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= 0.000223144; MAF= 0.02231%, 360/1613306 alleles, homozygotes = 2) and has highest observed frequency in the Admixed American population (AF= 0.00044979; MAF= 0.04498%, 27/60028 alleles, homozygotes = 1); grpmax FAF= 0.00031689.

v2.1

This variant is present in gnomAD v2.1 (AF= 0.000226663; MAF= 0.02267%, 64/282358 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.000695217; MAF= 0.06952%, 5/7192 alleles, homozygotes = 0); grpmax FAF= 0.00031301.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.022% · 360 / 1,613,306
2 hom · FAF 0.032%

Admixed American 27 / 60,028	0.045% 1 hom
European (non-Finnish) 302 / 1,179,438	0.026% 1 hom
Remaining individuals 14 / 62,448	0.022%
European (Finnish) 14 / 64,004	0.022%
African/African American 2 / 75,012	0.0027%
South Asian 1 / 91,064	0.0011%

+ 4 not observed (Amish, East Asian, Middle Eastern, Ashkenazi Jewish)

gnomAD v2.1

0.023% · 64 / 282,358
0 hom · FAF 0.031%

Remaining individuals 5 / 7,192	0.07%
Admixed American 17 / 35,418	0.048%
European (Finnish) 7 / 25,120	0.028%
European (non-Finnish) 34 / 128,982	0.026%
African/African American 1 / 24,760	0.004%

+ 3 not observed (Ashkenazi Jewish, East Asian, South Asian)

gnomAD v4 ↗ gnomAD v2 ↗

ClinVar

This variant has been reported in ClinVar as Likely benign (7 clinical laboratories) and as Uncertain significance (3 clinical laboratories) and as 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 oncogenicity for this specific variant: Unknown Oncogenic Effect (variant has not been individually curated).

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

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