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LYFE SCIENCES
Project: HERA
NM_001330437.1:c.1662G>A
p.Ala554=  ·  PTPN11
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Classification rationale
1

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.

clinvar ↗
2

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.

gnomad_v2 ↗ gnomad_v4 ↗ cspec ↗
3

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.

spliceai ↗ cspec ↗
Applied criteria
Met
Not met
Not assessed
N/A
Very strong
Strong
Moderate
Supporting
Pathogenic evidence
PVS
PVS1
PS
PS1
PS2
PS3
PS4
PM
PM1
PM2
PM3
PM4
PM5
PM6
PP
PP1
PP2
PP3
PP4
PP5
Benign evidence
BA
BA1
BS
BS1
BS2
BS3
BS4
BP
BP1
BP2
BP3
BP4
BP5
BP6
BP7
PVS1
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Rationale
Select a criterion to inspect its explanation.
Evidence used
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Gaps remaining
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Rule
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Publications
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Research and evidence
gnomAD v2.1 evidence
v2.1
gnomAD v4.1 evidence
v4.1
01
Population
gnomAD v2.1This 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.
gnomAD v4.1This 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.
gnomAD v2 ↗ gnomAD v4 ↗
ClinVar evidence
02
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 ↗
Functional evidence
03
Functional
OncoKB: Unknown Oncogenic Effect
OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.
OncoKB ↗
In silico evidence
04
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.18).
SpliceAI ↗
COSMIC evidence
05
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
COSMIC ↗
Cancer hotspots evidence
06
Cancer hotspots Not found
This variant does not lie in a statistically significant hotspot.
ResidueA554
Hotspots ↗