Classification rationale

BA1BS1BP6 Benign

PTPN11 c.1221A>G

The PTPN11 c.1221A>G (p.Gly407=) variant has not been identified in a statistically significant somatic hotspot and has been reported in ClinVar as Benign, including a benign expert-panel assertion from the ClinGen RASopathy Variant Curation Expert Panel.¹ In gnomAD, this variant exceeds the PTPN11 RASopathy benign population thresholds, with grpmax filtering allele frequencies of 0.11284% in v2.1 and 0.13502% in v4.1, both above the BA1 threshold of 0.05% and the BS1 threshold of 0.025%.² This synonymous variant does not change the encoded amino acid, and SpliceAI predicts no significant splice impact, with a maximum delta score of 0.02.³

BA1 + BS1 + BP6 → Benign

1 hotspots ↗clinvar ↗

2 gnomad_v2 ↗gnomad_v4 ↗cspec ↗

3 spliceai ↗

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= 9.11228e-05; MAF= 0.00911%, 147/1613208 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 0.00155945; MAF= 0.15594%, 142/91058 alleles, homozygotes = 0); grpmax FAF= 0.00135023.

v2.1

This variant is present in gnomAD v2.1 (AF= 0.000186931; MAF= 0.01869%, 47/251430 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 0.00147001; MAF= 0.14700%, 45/30612 alleles, homozygotes = 0); grpmax FAF= 0.00112836.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.0091% · 147 / 1,613,208
0 hom · FAF 0.14%

South Asian 142 / 91,058	0.16%
Remaining individuals 4 / 62,448	0.0064%
European (non-Finnish) 1 / 1,179,334	8.5e-05%

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

gnomAD v2.1

0.019% · 47 / 251,430
0 hom · FAF 0.11%

South Asian 45 / 30,612	0.15%
Remaining individuals 1 / 6,136	0.016%
Admixed American 1 / 34,592	0.0029%

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

gnomAD v4 ↗ gnomAD v2 ↗

ClinVar

This variant has been reported in ClinVar as Benign (8 clinical laboratories) and as Uncertain significance (1 clinical laboratory) 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 = 0.02).

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