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rs121913528

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1PM2PM5PP3PP5_Very_Strong

The NM_004985.5(KRAS):c.175G>T(p.Ala59Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD Genomes project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A59T) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

KRAS
NM_004985.5 missense

Scores

7
9
2

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P: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 15 ACMG points.

PM1
In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain 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 chr12-25227348-GC-AA is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2431456.Status of the report is criteria_provided_single_submitter, 1 stars.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.805
PP5
Variant 12-25227349-C-A is Pathogenic according to our data. Variant chr12-25227349-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 222075.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
KRASNM_033360.4 linkuse as main transcriptc.175G>T p.Ala59Ser missense_variant 3/6 ENST00000256078.10
KRASNM_004985.5 linkuse as main transcriptc.175G>T p.Ala59Ser missense_variant 3/5 ENST00000311936.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
KRASENST00000256078.10 linkuse as main transcriptc.175G>T p.Ala59Ser missense_variant 3/61 NM_033360.4 A1P01116-1
KRASENST00000311936.8 linkuse as main transcriptc.175G>T p.Ala59Ser missense_variant 3/51 NM_004985.5 P4P01116-2

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Pathogenic:2
Pathogenic, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenOct 01, 2018- -
Likely pathogenic, criteria provided, single submitterclinical testingMolecular Diagnostics Lab, Nemours Children's Health, DelawareJul 20, 2015- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.93
BayesDel_addAF
Pathogenic
0.23
D
BayesDel_noAF
Uncertain
0.090
Cadd
Pathogenic
27
Dann
Uncertain
1.0
Eigen
Uncertain
0.54
Eigen_PC
Uncertain
0.58
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.86
D;D
M_CAP
Uncertain
0.17
D
MetaRNN
Pathogenic
0.80
D;D
MetaSVM
Pathogenic
0.80
D
MutationAssessor
Benign
1.8
L;L
MutationTaster
Benign
1.0
D;D;D
PrimateAI
Pathogenic
0.89
D
PROVEAN
Uncertain
-2.6
D;D
REVEL
Pathogenic
0.78
Sift
Uncertain
0.020
D;D
Sift4G
Uncertain
0.022
D;D
Polyphen
0.27
B;P
Vest4
0.82
MutPred
0.75
Gain of catalytic residue at L56 (P = 0.0129);Gain of catalytic residue at L56 (P = 0.0129);
MVP
0.97
MPC
2.3
ClinPred
0.98
D
GERP RS
4.9
Varity_R
0.94
gMVP
0.85

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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: rs121913528; hg19: chr12-25380283; COSMIC: COSV55796966; COSMIC: COSV55796966; API