chr11-533799-T-G
Variant summary
Our verdict is Benign. Variant got -16 ACMG points: 2P and 18B. PM1BP4_ModerateBP6_Very_StrongBS1BS2
The NM_005343.4(HRAS):c.257A>C(p.Asn86Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000134 in 1,613,340 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★). Synonymous variant affecting the same amino acid position (i.e. N86N) has been classified as Likely benign.
Frequency
Consequence
NM_005343.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
HRAS | NM_005343.4 | c.257A>C | p.Asn86Thr | missense_variant | 3/6 | ENST00000311189.8 | |
HRAS | NM_176795.5 | c.257A>C | p.Asn86Thr | missense_variant | 3/6 | ENST00000417302.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HRAS | ENST00000311189.8 | c.257A>C | p.Asn86Thr | missense_variant | 3/6 | 1 | NM_005343.4 | P1 | |
HRAS | ENST00000417302.7 | c.257A>C | p.Asn86Thr | missense_variant | 3/6 | 5 | NM_176795.5 |
Frequencies
GnomAD3 genomes AF: 0.000296 AC: 45AN: 152112Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000183 AC: 46AN: 251296Hom.: 0 AF XY: 0.000155 AC XY: 21AN XY: 135894
GnomAD4 exome AF: 0.000117 AC: 171AN: 1461110Hom.: 0 Cov.: 34 AF XY: 0.000110 AC XY: 80AN XY: 726882
GnomAD4 genome AF: 0.000296 AC: 45AN: 152230Hom.: 0 Cov.: 33 AF XY: 0.000282 AC XY: 21AN XY: 74424
ClinVar
Submissions by phenotype
not specified Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Feb 15, 2018 | proposed classification - variant undergoing re-assessment, contact laboratory - |
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 15, 2021 | Variant summary: HRAS c.257A>C (p.Asn86Thr) results in a non-conservative amino acid change located in the Small GTP-binding protein domain (IPR005225) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00018 in 251296 control chromosomes. The observed variant frequency is approximately 36.6- fold the estimated maximal expected allele frequency for a pathogenic variant in HRAS causing Costello Syndrome phenotype (5e-06), strongly suggesting that the variant is benign. c.257A>C has been reported in the literature in an individual affected with pediatric cancer (e.g. Zhang_2015). This report does not provide unequivocal conclusions about association of the variant with Costello Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (benign/likely benign, n=3; uncertain significance, n=2). Based on the evidence outlined above, the variant was classified as benign. - |
not provided Uncertain:1Benign:1
Benign, criteria provided, single submitter | clinical testing | GeneDx | May 04, 2016 | This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. - |
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Sep 01, 2018 | - - |
Costello syndrome Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 29, 2024 | - - |
Noonan syndrome Benign:1
Likely benign, no assertion criteria provided | clinical testing | Service de Génétique Moléculaire, Hôpital Robert Debré | - | - - |
Hereditary cancer-predisposing syndrome Benign:1
Likely benign, criteria provided, single submitter | curation | Sema4, Sema4 | Jan 21, 2022 | - - |
HRAS-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Dec 06, 2019 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
RASopathy Benign:1
Benign, reviewed by expert panel | curation | ClinGen RASopathy Variant Curation Expert Panel | Apr 03, 2017 | The filtering allele frequency of the c.257A>C (p.Asn86Thr) variant in the HRAS gene is 0.07% for African chromosomes by the Exome Aggregation Consortium (12/10342 with 95% CI), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert panel for autosomal dominant RASopathy variants (BA1).This variant has been identified in a patient with an alternate molecular basis for disease (BP5; Partners LMM, GeneDx internal data GTR ID: 21766, 26957 ClinVar SCV000204177.4; SCV000207861.7). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied: BA1, BP5. - |
Noonan syndrome and Noonan-related syndrome Benign:1
Benign, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, The Hospital for Sick Children | Feb 01, 2020 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at