12-25206418-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_004985.5(KRAS):c.*3377C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.509 in 203,408 control chromosomes in the GnomAD database, including 27,720 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.49 (19377 hom., cov: 32)
  • Exomes 𝑓: 0.56 (8343 hom.)
• Consequence: KRAS NM_004985.5 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.99

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

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).
• BP6: Variant 12-25206418-G-A is Benign according to our data. Variant chr12-25206418-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 308076.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.779 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KRAS	NM_004985.5	c.*3377C>T		3_prime_UTR_variant	5/5	ENST00000311936.8
KRAS	NM_033360.4	c.*3498C>T		3_prime_UTR_variant	6/6	ENST00000256078.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KRAS	ENST00000256078.10	c.*3498C>T		3_prime_UTR_variant	6/6	1	NM_033360.4	A1
KRAS	ENST00000311936.8	c.*3377C>T		3_prime_UTR_variant	5/5	1	NM_004985.5	P4

Frequencies

GnomAD3 genomes AF: 0.493 AC: 74825 AN: 151788 Hom.: 19366 Cov.: 32

Gnomad AFR AF: 0.328

Gnomad AMI AF: 0.401

Gnomad AMR AF: 0.501

Gnomad ASJ AF: 0.625

Gnomad EAS AF: 0.800

Gnomad SAS AF: 0.669

Gnomad FIN AF: 0.544

Gnomad MID AF: 0.535

Gnomad NFE AF: 0.542

Gnomad OTH AF: 0.506

GnomAD4 exome AF: 0.557 AC: 28707 AN: 51502 Hom.: 8343 Cov.: 0 AF XY: 0.560 AC XY: 13379 AN XY: 23900

Gnomad4 AFR exome AF: 0.314

Gnomad4 AMR exome AF: 0.468

Gnomad4 ASJ exome AF: 0.631

Gnomad4 EAS exome AF: 0.781

Gnomad4 SAS exome AF: 0.662

Gnomad4 FIN exome AF: 0.504

Gnomad4 NFE exome AF: 0.522

Gnomad4 OTH exome AF: 0.526

GnomAD4 genome AF: 0.493 AC: 74866 AN: 151906 Hom.: 19377 Cov.: 32 AF XY: 0.499 AC XY: 37014 AN XY: 74238

Gnomad4 AFR AF: 0.328

Gnomad4 AMR AF: 0.501

Gnomad4 ASJ AF: 0.625

Gnomad4 EAS AF: 0.799

Gnomad4 SAS AF: 0.668

Gnomad4 FIN AF: 0.544

Gnomad4 NFE AF: 0.542

Gnomad4 OTH AF: 0.507

Alfa AF: 0.515 Hom.: 4206

Bravo AF: 0.482

Asia WGS AF: 0.689 AC: 2394 AN: 3472

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Noonan syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
Cadd	Benign	10
Dann	Benign	0.73

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1137188; hg19: chr12-25359352; COSMIC: COSV105058558; COSMIC: COSV105058558;