12-25225627-G-A
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PP3_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).
Frequency
Consequence
NM_004985.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
KRAS | NM_004985.5 | c.437C>T | p.Ala146Val | missense_variant | Exon 4 of 5 | ENST00000311936.8 | NP_004976.2 |
Ensembl
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
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Familial pancreatic carcinoma Pathogenic:1
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OCULOECTODERMAL SYNDROME, SOMATIC Pathogenic:1
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RASopathy Pathogenic:1
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. 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). This missense change has been observed in individuals with mosaic RASopathy (PMID: 26970110, 30891959). ClinVar contains an entry for this variant (Variation ID: 375962). 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. -
not provided Uncertain:1
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Encephalocraniocutaneous lipomatosis Other:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at