12-25206394-A-T

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.*3401T>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.503 in 199,826 control chromosomes in the GnomAD database, including 26,688 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 (19235 hom., cov: 31)
  • Exomes 𝑓: 0.54 (7453 hom.)
• Consequence: KRAS NM_004985.5 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -7.38

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=-1.02).
• BP6: Variant 12-25206394-A-T is Benign according to our data. Variant chr12-25206394-A-T is described in ClinVar as [Likely_benign]. Clinvar id is 308075.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.776 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KRAS	NM_004985.5	c.*3401T>A		3_prime_UTR_variant	5/5	ENST00000311936.8
KRAS	NM_033360.4	c.*3522T>A		3_prime_UTR_variant	6/6	ENST00000256078.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KRAS	ENST00000256078.10	c.*3522T>A		3_prime_UTR_variant	6/6	1	NM_033360.4	A1
KRAS	ENST00000311936.8	c.*3401T>A		3_prime_UTR_variant	5/5	1	NM_004985.5	P4

Frequencies

GnomAD3 genomes AF: 0.491 AC: 74505 AN: 151636 Hom.: 19224 Cov.: 31

Gnomad AFR AF: 0.327

Gnomad AMI AF: 0.400

Gnomad AMR AF: 0.498

Gnomad ASJ AF: 0.621

Gnomad EAS AF: 0.797

Gnomad SAS AF: 0.666

Gnomad FIN AF: 0.542

Gnomad MID AF: 0.535

Gnomad NFE AF: 0.540

Gnomad OTH AF: 0.504

GnomAD4 exome AF: 0.542 AC: 26067 AN: 48072 Hom.: 7453 Cov.: 0 AF XY: 0.544 AC XY: 12107 AN XY: 22238

Gnomad4 AFR exome AF: 0.292

Gnomad4 AMR exome AF: 0.449

Gnomad4 ASJ exome AF: 0.604

Gnomad4 EAS exome AF: 0.774

Gnomad4 SAS exome AF: 0.646

Gnomad4 FIN exome AF: 0.493

Gnomad4 NFE exome AF: 0.507

Gnomad4 OTH exome AF: 0.503

GnomAD4 genome AF: 0.491 AC: 74545 AN: 151754 Hom.: 19235 Cov.: 31 AF XY: 0.497 AC XY: 36853 AN XY: 74176

Gnomad4 AFR AF: 0.327

Gnomad4 AMR AF: 0.498

Gnomad4 ASJ AF: 0.621

Gnomad4 EAS AF: 0.797

Gnomad4 SAS AF: 0.665

Gnomad4 FIN AF: 0.542

Gnomad4 NFE AF: 0.540

Gnomad4 OTH AF: 0.504

Alfa AF: 0.515 Hom.: 2609

Bravo AF: 0.481

Asia WGS AF: 0.682 AC: 2368 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	-1.0
Cadd	Benign	0.13
Dann	Benign	0.11

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1137189; hg19: chr12-25359328; COSMIC: COSV105058557; COSMIC: COSV105058557;