Variant rs17851045 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PM5PP3PP5

The NM_004985.5(KRAS):c.183A>T(p.Gln61His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q61L) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

KRAS
NM_004985.5 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic no assertion criteria provided P:16

Conservation

PhyloP100: 2.81

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]

KRAS links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PM1

In a helix (size 2) in uniprot entity RASK_HUMAN there are 4 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 chr12-25227342-T-A is described in Lovd as [Likely_pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.766

PP5

Variant 12-25227341-T-A is Pathogenic according to our data. Variant chr12-25227341-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 45117.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr12-25227341-T-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KRAS	NM_033360.4 linkuse as main transcript	c.183A>T	p.Gln61His	missense_variant	3/6	ENST00000256078.10	NP_203524.1
KRAS	NM_004985.5 linkuse as main transcript	c.183A>T	p.Gln61His	missense_variant	3/5	ENST00000311936.8	NP_004976.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KRAS	ENST00000256078.10 linkuse as main transcript	c.183A>T	p.Gln61His	missense_variant	3/6	1	NM_033360.4	ENSP00000256078	A1	P01116-1
KRAS	ENST00000311936.8 linkuse as main transcript	c.183A>T	p.Gln61His	missense_variant	3/5	1	NM_004985.5	ENSP00000308495	P4	P01116-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:16

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Non-small cell lung carcinoma

Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Dec 07, 2007	- -
Pathogenic, no assertion criteria provided	literature only	Database of Curated Mutations (DoCM)	Oct 02, 2014	- -

Gastric adenocarcinoma

Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Squamous cell lung carcinoma

Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Malignant melanoma of skin

Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Acute myeloid leukemia

Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

B-cell chronic lymphocytic leukemia

Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Multiple myeloma

Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Malignant neoplasm of body of uterus

Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Pancreatic adenocarcinoma

Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Lung adenocarcinoma

Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Cerebral arteriovenous malformation

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital

- -

Transitional cell carcinoma of the bladder

Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Hepatocellular carcinoma

Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Thyroid tumor

Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Neoplasm of the large intestine

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.27

BayesDel_noAF

Pathogenic

0.14

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.87

.;D

Eigen

Uncertain

0.30

Eigen_PC

Uncertain

0.38

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.59

T;T

M_CAP

Uncertain

0.11

MetaRNN

Pathogenic

0.77

D;D

MetaSVM

Uncertain

0.26

MutationAssessor

Pathogenic

3.1

M;M

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Pathogenic

0.89

PROVEAN

Pathogenic

-4.4

D;D

REVEL

Pathogenic

0.65

Sift

Uncertain

0.0070

D;D

Sift4G

Uncertain

0.0020

D;D

Polyphen

0.41

B;B

Vest4

0.73

MutPred

0.66

Gain of catalytic residue at A59 (P = 0);Gain of catalytic residue at A59 (P = 0);

MVP

0.90

MPC

1.9

ClinPred

0.99

GERP RS

5.8

Varity_R

0.97

gMVP

0.94

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

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