12-25209843-A-T

Variant names:

• chr12-25209843-A-T
• rs1137282
• NM_004985.5:c.519T>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM2 PP2 BP4_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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.886
• Publications: 62 publications found

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]

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]

ACMG classification

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).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KRAS	NM_004985.5	c.519T>A	p.Asp173Glu	missense_variant	Exon 5 of 5	ENST00000311936.8	NP_004976.2
KRAS	NM_033360.4	c.*73T>A		3_prime_UTR_variant	Exon 6 of 6	ENST00000256078.10	NP_203524.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KRAS	ENST00000311936.8	c.519T>A	p.Asp173Glu	missense_variant	Exon 5 of 5	1	NM_004985.5	ENSP00000308495.3
KRAS	ENST00000256078.10	c.*73T>A		3_prime_UTR_variant	Exon 6 of 6	1	NM_033360.4	ENSP00000256078.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Uncertain	0.095	D
BayesDel_noAF	Benign	-0.10
CADD	Benign	17
DANN	Benign	0.90
DEOGEN2	Benign	0.0	.;.
Eigen	Benign	0.051
Eigen_PC	Benign	0.089
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.57	T;T
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.12	T;T
MetaSVM	Uncertain	0.23	D
MutationAssessor	Benign	0.0	.;.
PhyloP100		0.89
PROVEAN	Benign	0.19	N;N
REVEL	Benign	0.26
Sift	Benign	1.0	T;D
Sift4G	Benign	0.68	T;T
Vest4		0.13
ClinPred		0.37	T
GERP RS		3.4
Mutation Taster		=73/27	polymorphism

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

Other links and lift over

dbSNP: rs1137282; hg19: chr12-25362777;