Classification rationale

BP4BS1BP6 Likely Benign

PTPN11 c.1662G>A

The PTPN11 NM_001330437.1:c.1662G>A (p.(Ala554=)) variant has been reported in ClinVar as Benign, including an expert panel Benign assertion from the ClinGen RASopathy Variant Curation Expert Panel.¹ This variant is present in gnomAD, and its filtering allele frequency exceeds the PTPN11 RASopathy VCEP BS1 threshold of 0.025% in both datasets, with grpmax FAF 0.067298% in gnomAD v2.1 and 0.043105% in gnomAD v4.1.² SpliceAI predicts no significant splice impact for this synonymous variant, with a maximum delta score of 0.18, which supports benign computational evidence rather than a pathogenic splicing effect.³

BP4 + BS1 + BP6 → Likely Benign

1 clinvar ↗

2 gnomad_v2 ↗gnomad_v4 ↗cspec ↗

3 spliceai ↗cspec ↗

Gene diagram · NM_001330437.1 · variants mapped to exon structure

PTPN11 NM_001330437.1

Fetching transcript structure from UCSC…

Applied criteria · 3 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= 2.85051e-05; MAF= 0.00285%, 46/1613744 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 0.00058345; MAF= 0.05835%, 35/59988 alleles, homozygotes = 0); grpmax FAF= 0.00043105.

v2.1

This variant is present in gnomAD v2.1 (AF= 0.000139413; MAF= 0.01394%, 35/251052 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 0.000925123; MAF= 0.09251%, 32/34590 alleles, homozygotes = 0); grpmax FAF= 0.00067298.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.0029% · 46 / 1,613,744
0 hom · FAF 0.043%

Admixed American 35 / 59,988	0.058%
Remaining individuals 2 / 62,468	0.0032%
East Asian 1 / 44,894	0.0022%
South Asian 1 / 91,070	0.0011%
European (non-Finnish) 7 / 1,179,846	0.00059%

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

gnomAD v2.1

0.014% · 35 / 251,052
0 hom · FAF 0.067%

Admixed American 32 / 34,590	0.093%
East Asian 2 / 18,392	0.011%
European (non-Finnish) 1 / 113,360	0.00088%

+ 5 not observed (African/African American, Ashkenazi Jewish, European (Finnish), Remaining individuals, South Asian)

gnomAD v4 ↗ gnomAD v2 ↗

ClinVar

This variant has been reported in ClinVar as Benign (6 clinical laboratories) and as Likely benign (2 clinical laboratories) and as Benign by ClinGen RASopathy Variant Curation Expert Panel (expert panel).

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.18).

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 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