chr12-25205484-T-C

Variant names:

• chr12-25205484-T-C
• rs61764374
• NM_004985.5:c.*4311A>G

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4 BP6_Very_Strong BA1

The NM_004985.5(KRAS):​c.*4311A>G variant causes a 3 prime UTR change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0388 in 215,318 control chromosomes in the GnomAD database, including 190 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.037 (126 hom., cov: 32)
  • Exomes 𝑓: 0.042 (64 hom.)
• Consequence: KRAS NM_004985.5 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 7.35
• Publications: 6 publications found

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

Our verdict: Benign. The variant received -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.18).
• BP6: Variant 12-25205484-T-C is Benign according to our data. Variant chr12-25205484-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 308057.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.057 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KRAS	NM_004985.5	c.*4311A>G		3_prime_UTR_variant	Exon 5 of 5	ENST00000311936.8	NP_004976.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KRAS	ENST00000311936.8	c.*4311A>G		3_prime_UTR_variant	Exon 5 of 5	1	NM_004985.5	ENSP00000308495.3

Frequencies

GnomAD3 genomes AF: 0.0374 AC: 5643 AN: 151002 Hom.: 127 Cov.: 32

Gnomad AFR AF: 0.00981

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.0299

Gnomad ASJ AF: 0.0504

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0201

Gnomad FIN AF: 0.0400

Gnomad MID AF: 0.0669

Gnomad NFE AF: 0.0585

Gnomad OTH AF: 0.0447

GnomAD4 exome AF: 0.0421 AC: 2705 AN: 64194 Hom.: 64 Cov.: 0 AF XY: 0.0437 AC XY: 1297 AN XY: 29664

African (AFR) AF: 0.00637 AC: 19 AN: 2982

American (AMR) AF: 0.0252 AC: 48 AN: 1906

Ashkenazi Jewish (ASJ) AF: 0.0551 AC: 225 AN: 4082

East Asian (EAS) AF: 0.000108 AC: 1 AN: 9268

South Asian (SAS) AF: 0.0258 AC: 14 AN: 542

European-Finnish (FIN) AF: 0.0445 AC: 21 AN: 472

Middle Eastern (MID) AF: 0.0682 AC: 27 AN: 396

European-Non Finnish (NFE) AF: 0.0542 AC: 2123 AN: 39174

Other (OTH) AF: 0.0423 AC: 227 AN: 5372

GnomAD4 genome AF: 0.0373 AC: 5640 AN: 151124 Hom.: 126 Cov.: 32 AF XY: 0.0351 AC XY: 2597 AN XY: 73888

African (AFR) AF: 0.00978 AC: 396 AN: 40494

American (AMR) AF: 0.0298 AC: 455 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.0504 AC: 175 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5194

South Asian (SAS) AF: 0.0201 AC: 97 AN: 4828

European-Finnish (FIN) AF: 0.0400 AC: 424 AN: 10590

Middle Eastern (MID) AF: 0.0685 AC: 20 AN: 292

European-Non Finnish (NFE) AF: 0.0585 AC: 3977 AN: 67982

Other (OTH) AF: 0.0433 AC: 91 AN: 2104

Alfa AF: 0.0518 Hom.: 41

Bravo AF: 0.0339

Asia WGS AF: 0.0140 AC: 47 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Noonan syndrome Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.18
CADD	Benign	17
DANN	Benign	0.92
PhyloP100		7.3
Mutation Taster		=81/19	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs61764374; hg19: chr12-25358418;