rs1057519725
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PM5PP3_ModeratePP5
The NM_004985.5(KRAS):c.437C>T(p.Ala146Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000031 in 1,612,722 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. A146S) has been classified as Likely 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.437C>T | p.Ala146Val | missense_variant | 4/6 | ENST00000256078.10 | |
KRAS | NM_004985.5 | c.437C>T | p.Ala146Val | missense_variant | 4/5 | ENST00000311936.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KRAS | ENST00000256078.10 | c.437C>T | p.Ala146Val | missense_variant | 4/6 | 1 | NM_033360.4 | A1 | |
KRAS | ENST00000311936.8 | c.437C>T | p.Ala146Val | missense_variant | 4/5 | 1 | NM_004985.5 | P4 | |
ENST00000620933.1 | n.525G>A | non_coding_transcript_exon_variant | 1/1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000658 AC: 1AN: 151910Hom.: 0 Cov.: 31
GnomAD4 exome AF: 0.00000274 AC: 4AN: 1460812Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3AN XY: 726776
GnomAD4 genome ? AF: 0.00000658 AC: 1AN: 151910Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 74190
ClinVar
Submissions by phenotype
Malignant tumor of urinary bladder Pathogenic:1
Pathogenic, no assertion criteria provided | research | Laboratory of Urology, Hospital Clinic de Barcelona | - | - - |
Thyroid tumor 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 | Mar 09, 2022 | - - |
Neoplasm of the large intestine 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 | Jul 25, 2022 | ClinVar contains an entry for this variant (Variation ID: 375962). 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. Experimental studies have shown that this missense change affects KRAS function (PMID: 30448735). This variant disrupts the p.Ala146 amino acid residue in KRAS. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. This missense change has been observed in individuals with mosaic RASopathy (PMID: 26970110, 30891959). This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 146 of the KRAS protein (p.Ala146Val). This variant is not present in population databases (gnomAD no frequency). - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn | Nov 14, 2023 | - - |
Encephalocraniocutaneous lipomatosis Other:1
not provided, no classification provided | literature only | GeneReviews | - | - - |
Non-small cell lung carcinoma Other:1
not provided, no classification provided | literature only | Database of Curated Mutations (DoCM) | Mar 10, 2016 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at