rs9266

chr12-25209283-A-G

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_004985.5(KRAS):c.*512T>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 0.55 in 644,948 control chromosomes in the GnomAD database, including 100,913 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 (19406 hom., cov: 31)
  • Exomes 𝑓: 0.57 (81507 hom.)
• Consequence: KRAS NM_004985.5 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.472

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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.28).
• BP6: Variant 12-25209283-A-G is Benign according to our data. Variant chr12-25209283-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 308118.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-25209283-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.781 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KRAS	NM_004985.5	c.*512T>C		3_prime_UTR_variant	5/5	ENST00000311936.8
KRAS	NM_033360.4	c.*633T>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.*633T>C		3_prime_UTR_variant	6/6	1	NM_033360.4	A1
KRAS	ENST00000311936.8	c.*512T>C		3_prime_UTR_variant	5/5	1	NM_004985.5	P4

Frequencies

GnomAD3 genomes AF: 0.493 AC: 74841 AN: 151788 Hom.: 19394 Cov.: 31

Gnomad AFR AF: 0.328

Gnomad AMI AF: 0.399

Gnomad AMR AF: 0.501

Gnomad ASJ AF: 0.624

Gnomad EAS AF: 0.801

Gnomad SAS AF: 0.669

Gnomad FIN AF: 0.543

Gnomad MID AF: 0.535

Gnomad NFE AF: 0.542

Gnomad OTH AF: 0.506

GnomAD3 exomes AF: 0.581 AC: 61555 AN: 106036 Hom.: 18269 AF XY: 0.584 AC XY: 34276 AN XY: 58664

Gnomad AFR exome AF: 0.324

Gnomad AMR exome AF: 0.546

Gnomad ASJ exome AF: 0.632

Gnomad EAS exome AF: 0.806

Gnomad SAS exome AF: 0.665

Gnomad FIN exome AF: 0.560

Gnomad NFE exome AF: 0.542

Gnomad OTH exome AF: 0.558

GnomAD4 exome AF: 0.567 AC: 279771 AN: 493042 Hom.: 81507 Cov.: 4 AF XY: 0.572 AC XY: 152847 AN XY: 267114

Gnomad4 AFR exome AF: 0.328

Gnomad4 AMR exome AF: 0.530

Gnomad4 ASJ exome AF: 0.639

Gnomad4 EAS exome AF: 0.797

Gnomad4 SAS exome AF: 0.655

Gnomad4 FIN exome AF: 0.563

Gnomad4 NFE exome AF: 0.541

Gnomad4 OTH exome AF: 0.554

GnomAD4 genome AF: 0.493 AC: 74883 AN: 151906 Hom.: 19406 Cov.: 31 AF XY: 0.499 AC XY: 37018 AN XY: 74242

Gnomad4 AFR AF: 0.328

Gnomad4 AMR AF: 0.501

Gnomad4 ASJ AF: 0.624

Gnomad4 EAS AF: 0.801

Gnomad4 SAS AF: 0.668

Gnomad4 FIN AF: 0.543

Gnomad4 NFE AF: 0.542

Gnomad4 OTH AF: 0.507

Alfa AF: 0.541 Hom.: 46975

Bravo AF: 0.482

Asia WGS AF: 0.691 AC: 2401 AN: 3474

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

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

- -

Noonan syndrome and Noonan-related syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jul 13, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.28
Cadd	Benign	11
Dann	Benign	0.86

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs9266; hg19: chr12-25362217;