NM_004985.5:c.38G>A
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PM5PP3_ModeratePP5_Very_Strong
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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G13C) has been classified as Pathogenic.
Frequency
Consequence
NM_004985.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
KRAS | NM_004985.5 | c.38G>A | p.Gly13Asp | missense_variant | Exon 2 of 5 | ENST00000311936.8 | NP_004976.2 |
Ensembl
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
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Autoimmune lymphoproliferative syndrome type 4 Pathogenic:1
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Inborn genetic diseases Pathogenic:1
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Nevus sebaceous Pathogenic:1
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Breast adenocarcinoma Pathogenic:1
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Familial pancreatic carcinoma Pathogenic:1
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OCULOECTODERMAL SYNDROME, SOMATIC Pathogenic:1
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KRAS-related disorder Pathogenic:1
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, indicating this variant is rare. This variant is interpreted as pathogenic. -
Juvenile myelomonocytic leukemia Pathogenic:1
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Non-small cell lung carcinoma Pathogenic:1
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RASopathy Pathogenic:1
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 performed at Invitae incorporating data from internal and/or published experimental studies (Invitae) indicates that this missense variant is expected to disrupt KRAS function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -
Noonan syndrome and Noonan-related syndrome Pathogenic:1
This missense variant results in a change from glycine to aspartic acid at amino acid position 13. It has been previously reported in a somatic mosaic state in individuals with myelodysplastic/myeloproliferative disease (PMID: 22571758). It was also identified in a patient with Oculoectodermal syndrome (PMID: 25808193) and found in a case of RAS-associated autoimmune leukoproliferative disorder (PMID: 32441320). This variant is in the P-loop and mutational hotspot defined by ClinGen expert panel. Additionally the same amino acid change, p.Gly13Asp, in the HRAS gene has been reported as pathogenic in several patients (SickKids, internal data). This variant is observed at an allele frequency of 0.00031% in population controls of the Genome Aggregation Database (gnomAD). Based on the evidence above, this variant is classified as pathogenic (PS1, PS4_m, PM1, PM2, PP3, PP5). -
Encephalocraniocutaneous lipomatosis Other:1
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Neoplasm Other:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at