Genetic Variant KRAS:p.Asp173Glu (chr12-25209843-A-T) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM2PP2BP4_Moderate

The NM_004985.5(KRAS):c.519T>A(p.Asp173Glu) 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 benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. D173D) has been classified as Benign.

Frequency

Genomes: not found (cov: 33)

Consequence

KRAS
NM_004985.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.886

Publications

62 publications found

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:

ETFRF1 (HGNC:27052): (electron transfer flavoprotein regulatory factor 1) Involved in respiratory electron transport chain. Located in mitochondrion. [provided by Alliance of Genome Resources, Apr 2022]

ETFRF1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 65 curated pathogenic missense variants (we use a threshold of 10). The gene has 3 curated benign missense variants. Gene score misZ: 2.3177 (below the threshold of 3.09). Trascript score misZ: 3.0857 (below the threshold of 3.09). GenCC associations: The gene is linked to cardiofaciocutaneous syndrome, cardiofaciocutaneous syndrome 2, Noonan syndrome 3, Noonan syndrome, Costello syndrome, linear nevus sebaceous syndrome.

BP4

Computational evidence support a benign effect (MetaRNN=0.11923838).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004985.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
KRAS	NM_004985.5	MANE Select	c.519T>A	p.Asp173Glu	missense	Exon 5 of 5	NP_004976.2
KRAS	NM_033360.4	MANE Plus Clinical	c.*73T>A		3_prime_UTR	Exon 6 of 6	NP_203524.1
KRAS	NM_001369787.1		c.519T>A	p.Asp173Glu	missense	Exon 5 of 5	NP_001356716.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
KRAS	ENST00000311936.8	TSL:1 MANE Select	c.519T>A	p.Asp173Glu	missense	Exon 5 of 5	ENSP00000308495.3
KRAS	ENST00000256078.10	TSL:1 MANE Plus Clinical	c.*73T>A		3_prime_UTR	Exon 6 of 6	ENSP00000256078.5
KRAS	ENST00000685328.1		c.519T>A	p.Asp173Glu	missense	Exon 5 of 5	ENSP00000508921.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.087

BayesDel_addAF

Uncertain

0.095

BayesDel_noAF

Benign

-0.10

CADD

Benign

(source)

DANN

Benign

0.90

Eigen

Benign

0.051

Eigen_PC

Benign

0.089

FATHMM_MKL

Uncertain

0.79

LIST_S2

Benign

0.57

M_CAP

Uncertain

0.17

MetaRNN

Benign

0.12

MetaSVM

Uncertain

0.23

PhyloP100

0.89

PROVEAN

Benign

0.19

REVEL

Benign

0.26

Sift

Benign

1.0

Sift4G

Benign

0.68

Polyphen

0.76

Vest4

0.13

MutPred

0.21

Gain of helix (P = 0.0325)

MVP

0.77

ClinPred

0.37

GERP RS

3.4

Mutation Taster

=73/27

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over