chr12-25245347-C-T
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PM5PP3_ModeratePP5
The NM_004985.5(KRAS):c.38G>A(p.Gly13Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000031 in 1,612,796 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G13A) has been classified as Pathogenic.
Frequency
Consequence
NM_004985.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KRAS | NM_033360.4 | c.38G>A | p.Gly13Asp | missense_variant | 2/6 | ENST00000256078.10 | |
KRAS | NM_004985.5 | c.38G>A | p.Gly13Asp | missense_variant | 2/5 | ENST00000311936.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KRAS | ENST00000256078.10 | c.38G>A | p.Gly13Asp | missense_variant | 2/6 | 1 | NM_033360.4 | A1 | |
KRAS | ENST00000311936.8 | c.38G>A | p.Gly13Asp | missense_variant | 2/5 | 1 | NM_004985.5 | P4 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152170Hom.: 0 Cov.: 32
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1460626Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 726524
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152170Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74334
ClinVar
Submissions by phenotype
not provided Pathogenic:5
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Sep 09, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Feb 01, 2020 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | - - |
Pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Likely pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Non-small cell lung carcinoma Pathogenic:2
Pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | Oct 02, 2014 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Nov 02, 2011 | - - |
Autoimmune lymphoproliferative syndrome type 4 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jul 01, 2015 | - - |
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 19, 2018 | - - |
Nevus sebaceous Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Equipe Genetique des Anomalies du Developpement, Université de Bourgogne | - | - - |
Breast adenocarcinoma Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jul 01, 2015 | - - |
Ovarian neoplasm Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | Oct 02, 2014 | - - |
OCULOECTODERMAL SYNDROME, SOMATIC Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jul 01, 2015 | - - |
Acute myeloid leukemia Pathogenic:1
Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | Oct 02, 2014 | - - |
KRAS-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Nov 15, 2023 | The KRAS c.38G>A variant is predicted to result in the amino acid substitution p.Gly13Asp. This variant has been reported as a mosaic change in two patients with RAS-associated autoimmune leukoproliferative disorder, oculoectodermal syndrome/encephalocraniocutaneous lipomatosis, and an individual with myelodysplastic/myeloproliferative disease who was also positive for additional variants (Takagi et al. 2011. PubMed ID: 21063026; Peacock et al. 2015. PubMed ID: 25808193; Moog and Moog. 2022. PubMed ID: 35099867; Patient 2, Ismael et al. 2012. PubMed ID: 22571758). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic. - |
Juvenile myelomonocytic leukemia Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jul 01, 2015 | - - |
Thyroid tumor Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | Oct 02, 2014 | - - |
RASopathy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Aug 19, 2023 | This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 13 of the KRAS protein (p.Gly13Asp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with oculoectodermal syndrome, as a mosaic variant (PMID: 25808193). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 12580). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt KRAS protein function. For these reasons, this variant has been classified as Pathogenic. - |
Neoplasm of the large intestine Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | Mar 10, 2016 | - - |
Noonan syndrome and Noonan-related syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, The Hospital for Sick Children | Dec 01, 2019 | - - |
Encephalocraniocutaneous lipomatosis Other:1
not provided, no classification provided | literature only | GeneReviews | - | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at