12-25205716-A-T

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.*4079T>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 0.519 in 222,762 control chromosomes in the GnomAD database, including 31,530 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 (19367 hom., cov: 31)
  • Exomes 𝑓: 0.58 (12163 hom.)
• Consequence: KRAS NM_004985.5 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.02

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=-0.82).
• BP6: Variant 12-25205716-A-T is Benign according to our data. Variant chr12-25205716-A-T is described in ClinVar as [Likely_benign]. Clinvar id is 308059.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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.*4079T>A		3_prime_UTR_variant	5/5	ENST00000311936.8
KRAS	NM_033360.4	c.*4200T>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.*4200T>A		3_prime_UTR_variant	6/6	1	NM_033360.4	A1
KRAS	ENST00000311936.8	c.*4079T>A		3_prime_UTR_variant	5/5	1	NM_004985.5	P4

Frequencies

GnomAD3 genomes AF: 0.493 AC: 74764 AN: 151734 Hom.: 19356 Cov.: 31

Gnomad AFR AF: 0.328

Gnomad AMI AF: 0.398

Gnomad AMR AF: 0.500

Gnomad ASJ AF: 0.624

Gnomad EAS AF: 0.800

Gnomad SAS AF: 0.669

Gnomad FIN AF: 0.544

Gnomad MID AF: 0.535

Gnomad NFE AF: 0.541

Gnomad OTH AF: 0.506

GnomAD4 exome AF: 0.576 AC: 40809 AN: 70910 Hom.: 12163 Cov.: 0 AF XY: 0.577 AC XY: 18923 AN XY: 32786

Gnomad4 AFR exome AF: 0.335

Gnomad4 AMR exome AF: 0.498

Gnomad4 ASJ exome AF: 0.642

Gnomad4 EAS exome AF: 0.792

Gnomad4 SAS exome AF: 0.664

Gnomad4 FIN exome AF: 0.500

Gnomad4 NFE exome AF: 0.543

Gnomad4 OTH exome AF: 0.554

GnomAD4 genome AF: 0.493 AC: 74805 AN: 151852 Hom.: 19367 Cov.: 31 AF XY: 0.498 AC XY: 36962 AN XY: 74192

Gnomad4 AFR AF: 0.328

Gnomad4 AMR AF: 0.500

Gnomad4 ASJ AF: 0.624

Gnomad4 EAS AF: 0.800

Gnomad4 SAS AF: 0.668

Gnomad4 FIN AF: 0.544

Gnomad4 NFE AF: 0.541

Gnomad4 OTH AF: 0.507

Alfa AF: 0.516 Hom.: 2615

Bravo AF: 0.482

Asia WGS AF: 0.690 AC: 2401 AN: 3478

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

Dec 23, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
Cadd	Benign	10
Dann	Benign	0.64

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs12245; hg19: chr12-25358650;