11-532700-C-T
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 2P and 7B. PM1BP4_ModerateBS1_SupportingBS2
The NM_005343.4(HRAS):c.506G>A(p.Arg169Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000415 in 1,613,070 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R169W) has been classified as Uncertain significance.
Frequency
Consequence
NM_005343.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -5 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000657 AC: 10AN: 152250Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000281 AC: 7AN: 249282Hom.: 0 AF XY: 0.0000222 AC XY: 3AN XY: 135174
GnomAD4 exome AF: 0.0000390 AC: 57AN: 1460820Hom.: 0 Cov.: 32 AF XY: 0.0000344 AC XY: 25AN XY: 726736
GnomAD4 genome AF: 0.0000657 AC: 10AN: 152250Hom.: 0 Cov.: 33 AF XY: 0.0000538 AC XY: 4AN XY: 74382
ClinVar
Submissions by phenotype
Costello syndrome Uncertain:2
This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 169 of the HRAS protein (p.Arg169Gln). This variant is present in population databases (rs142218590, gnomAD 0.01%). This missense change has been observed in individual(s) with an unspecified cancer (PMID: 25742471). ClinVar contains an entry for this variant (Variation ID: 180856). Invitae Evidence Modeling incorporating data from in vitro experimental studies (internal data) indicates that this missense variant is not expected to disrupt HRAS function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
not provided Uncertain:1
The R169Q variant has not been published in association with the Noonan syndrome spectrum to our knowledge; the variant has been observed as a germline variant in an individual with lung cancer but no reported other phenotype (Marks et al., 2007). It was observed to co-occur with the M269T pathogenic variant in the SOS1 gene in a patient at GeneDx. The variant is observed in 1/10172 (0.01%) alleles from individuals of African background in the ExAC dataset (Lek et al., 2016). R169Q is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species; however, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. In summary, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. -
Hereditary cancer-predisposing syndrome Uncertain:1
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Malignant tumor of urinary bladder;C0334082:Epidermal nevus;C0587248:Costello syndrome;C1842036:Large congenital melanocytic nevus;C4225426:Thyroid cancer, nonmedullary, 2;C4552097:Linear nevus sebaceous syndrome Uncertain:1
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HRAS-related disorder Uncertain:1
The HRAS c.506G>A variant is predicted to result in the amino acid substitution p.Arg169Gln. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.016% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-532700-C-T) and is interpreted as uncertain in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/180856/). Although we suspect this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at