rs61764370

Positions:

• chr12-25207290-A-C
• chr12-25207290-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004985.5(KRAS):​c.*2505T>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0642 in 195,932 control chromosomes in the GnomAD database, including 528 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.062 (390 hom., cov: 31)
  • Exomes 𝑓: 0.073 (138 hom.)
• Consequence: KRAS NM_004985.5 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.836

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 12-25207290-A-C is Benign according to our data. Variant chr12-25207290-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 308084.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-25207290-A-C is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0913 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KRAS	NM_004985.5	c.*2505T>G		3_prime_UTR_variant	5/5	ENST00000311936.8
KRAS	NM_033360.4	c.*2626T>G		3_prime_UTR_variant	6/6	ENST00000256078.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KRAS	ENST00000256078.10	c.*2626T>G		3_prime_UTR_variant	6/6	1	NM_033360.4	A1
KRAS	ENST00000311936.8	c.*2505T>G		3_prime_UTR_variant	5/5	1	NM_004985.5	P4

Frequencies

GnomAD3 genomes AF: 0.0617 AC: 9391 AN: 152092 Hom.: 389 Cov.: 31

Gnomad AFR AF: 0.0189

Gnomad AMI AF: 0.112

Gnomad AMR AF: 0.0790

Gnomad ASJ AF: 0.0923

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.0189

Gnomad FIN AF: 0.0348

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.0932

Gnomad OTH AF: 0.0773

GnomAD4 exome AF: 0.0726 AC: 3176 AN: 43722 Hom.: 138 Cov.: 0 AF XY: 0.0744 AC XY: 1516 AN XY: 20390

Gnomad4 AFR exome AF: 0.0251

Gnomad4 AMR exome AF: 0.0706

Gnomad4 ASJ exome AF: 0.0966

Gnomad4 EAS exome AF: 0.000137

Gnomad4 SAS exome AF: 0.00847

Gnomad4 FIN exome AF: 0.0833

Gnomad4 NFE exome AF: 0.0936

Gnomad4 OTH exome AF: 0.0791

GnomAD4 genome AF: 0.0617 AC: 9396 AN: 152210 Hom.: 390 Cov.: 31 AF XY: 0.0588 AC XY: 4375 AN XY: 74424

Gnomad4 AFR AF: 0.0190

Gnomad4 AMR AF: 0.0789

Gnomad4 ASJ AF: 0.0923

Gnomad4 EAS AF: 0.000580

Gnomad4 SAS AF: 0.0195

Gnomad4 FIN AF: 0.0348

Gnomad4 NFE AF: 0.0932

Gnomad4 OTH AF: 0.0764

Alfa AF: 0.0702 Hom.: 74

Bravo AF: 0.0638

Asia WGS AF: 0.0120 AC: 41 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Noonan syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

RASopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 22, 2024

- -

Noonan syndrome and Noonan-related syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Nov 01, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	4.2
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: rs61764370; hg19: chr12-25360224;