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

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

KRAS
NM_004985.5 missense

Scores

11
7
1

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:16O:2

Conservation

PhyloP100: 7.89
Variant links:
Genes affected
KRAS (HGNC:6407): (KRAS proto-oncogene, GTPase) This gene, a Kirsten ras oncogene homolog from the mammalian ras gene family, encodes a protein that is a member of the small GTPase superfamily. A single amino acid substitution is responsible for an activating mutation. The transforming protein that results is implicated in various malignancies, including lung adenocarcinoma, mucinous adenoma, ductal carcinoma of the pancreas and colorectal carcinoma. Alternative splicing leads to variants encoding two isoforms that differ in the C-terminal region. [provided by RefSeq, Jul 2008]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PM1
In a chain GTPase KRas, N-terminally processed (size 184) in uniprot entity RASK_HUMAN there are 29 pathogenic changes around while only 0 benign (100%) in NM_004985.5
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr12-25245348-C-A is described in Lovd as [Pathogenic].
PP3
MetaRNN computational evidence supports a deleterious effect, 0.901
PP5
Variant 12-25245347-C-T is Pathogenic according to our data. Variant chr12-25245347-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 12580.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-25245347-C-T is described in Lovd as [Pathogenic]. Variant chr12-25245347-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
KRASNM_004985.5 linkc.38G>A p.Gly13Asp missense_variant Exon 2 of 5 ENST00000311936.8 NP_004976.2 P01116-2A0A024RAV5

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
KRASENST00000311936.8 linkc.38G>A p.Gly13Asp missense_variant Exon 2 of 5 1 NM_004985.5 ENSP00000308495.3 P01116-2

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152170
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000441
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1460626
Hom.:
0
Cov.:
31
AF XY:
0.00000138
AC XY:
1
AN XY:
726524
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000180
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000197
AC:
3
AN:
152170
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74334
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000441
Gnomad4 OTH
AF:
0.00

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:16Other:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Pathogenic:5
Sep 09, 2021
Revvity Omics, Revvity
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Feb 01, 2020
CeGaT Center for Human Genetics Tuebingen
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

-
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Significance: Likely pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

-
Department of Pathology and Laboratory Medicine, Sinai Health System
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Autoimmune lymphoproliferative syndrome type 4 Pathogenic:1
Jul 01, 2015
OMIM
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

Inborn genetic diseases Pathogenic:1
Jul 19, 2018
Ambry Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Nevus sebaceous Pathogenic:1
-
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Breast adenocarcinoma Pathogenic:1
Jul 01, 2015
OMIM
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

Familial pancreatic carcinoma Pathogenic:1
Dec 18, 2024
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

OCULOECTODERMAL SYNDROME, SOMATIC Pathogenic:1
Jul 01, 2015
OMIM
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

KRAS-related disorder Pathogenic:1
May 03, 2024
PreventionGenetics, part of Exact Sciences
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

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
Jul 01, 2015
OMIM
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

Non-small cell lung carcinoma Pathogenic:1
Nov 02, 2011
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

RASopathy Pathogenic:1
Mar 22, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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
Feb 11, 2023
Genome Diagnostics Laboratory, The Hospital for Sick Children
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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
-
GeneReviews
Significance: not provided
Review Status: no classification provided
Collection Method: literature only

- -

Neoplasm Other:1
Mar 04, 2025
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Significance: -
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.43
D
BayesDel_noAF
Pathogenic
0.38
CADD
Pathogenic
28
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.90
.;.;D;.
Eigen
Uncertain
0.65
Eigen_PC
Pathogenic
0.69
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.86
D;D;D;D
M_CAP
Uncertain
0.23
D
MetaRNN
Pathogenic
0.90
D;D;D;D
MetaSVM
Uncertain
0.57
D
MutationAssessor
Pathogenic
3.0
M;.;M;.
PrimateAI
Pathogenic
0.93
D
PROVEAN
Pathogenic
-5.4
D;D;D;D
REVEL
Pathogenic
0.83
Sift
Uncertain
0.029
D;D;D;D
Sift4G
Uncertain
0.024
D;D;D;D
Polyphen
0.21
B;.;P;.
Vest4
0.95
MutPred
0.72
Gain of catalytic residue at A11 (P = 0);Gain of catalytic residue at A11 (P = 0);Gain of catalytic residue at A11 (P = 0);Gain of catalytic residue at A11 (P = 0);
MVP
0.97
MPC
2.4
ClinPred
0.99
D
GERP RS
5.7
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.6
Varity_R
0.91
gMVP
0.95

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs112445441; hg19: chr12-25398281; COSMIC: COSV55497388; API