12-25206035-T-G

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.*3760A>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.403 in 207,204 control chromosomes in the GnomAD database, including 19,688 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.38 (12802 hom., cov: 31)
  • Exomes 𝑓: 0.47 (6886 hom.)
• Consequence: KRAS NM_004985.5 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.36

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=-0.8).
• BP6: Variant 12-25206035-T-G is Benign according to our data. Variant chr12-25206035-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 308066.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.771 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KRAS	NM_004985.5	c.*3760A>C		3_prime_UTR_variant	5/5	ENST00000311936.8
KRAS	NM_033360.4	c.*3881A>C		3_prime_UTR_variant	6/6	ENST00000256078.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KRAS	ENST00000256078.10	c.*3881A>C		3_prime_UTR_variant	6/6	1	NM_033360.4	A1
KRAS	ENST00000311936.8	c.*3760A>C		3_prime_UTR_variant	5/5	1	NM_004985.5	P4

Frequencies

GnomAD3 genomes AF: 0.377 AC: 57213 AN: 151730 Hom.: 12800 Cov.: 31

Gnomad AFR AF: 0.140

Gnomad AMI AF: 0.377

Gnomad AMR AF: 0.443

Gnomad ASJ AF: 0.526

Gnomad EAS AF: 0.792

Gnomad SAS AF: 0.483

Gnomad FIN AF: 0.436

Gnomad MID AF: 0.453

Gnomad NFE AF: 0.450

Gnomad OTH AF: 0.396

GnomAD4 exome AF: 0.475 AC: 26271 AN: 55356 Hom.: 6886 Cov.: 0 AF XY: 0.477 AC XY: 12214 AN XY: 25602

Gnomad4 AFR exome AF: 0.141

Gnomad4 AMR exome AF: 0.425

Gnomad4 ASJ exome AF: 0.519

Gnomad4 EAS exome AF: 0.779

Gnomad4 SAS exome AF: 0.478

Gnomad4 FIN exome AF: 0.444

Gnomad4 NFE exome AF: 0.432

Gnomad4 OTH exome AF: 0.433

GnomAD4 genome AF: 0.377 AC: 57225 AN: 151848 Hom.: 12802 Cov.: 31 AF XY: 0.383 AC XY: 28384 AN XY: 74180

Gnomad4 AFR AF: 0.140

Gnomad4 AMR AF: 0.443

Gnomad4 ASJ AF: 0.526

Gnomad4 EAS AF: 0.792

Gnomad4 SAS AF: 0.482

Gnomad4 FIN AF: 0.436

Gnomad4 NFE AF: 0.450

Gnomad4 OTH AF: 0.398

Alfa AF: 0.300 Hom.: 904

Bravo AF: 0.369

Asia WGS AF: 0.593 AC: 2051 AN: 3462

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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
Cadd	Benign	5.6
Dann	Benign	0.75

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1137196; hg19: chr12-25358969;