12-25206009-T-C

Variant names:

• chr12-25206009-T-C
• rs8720
• NM_004985.5:c.*3786A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004985.5(KRAS):​c.*3786A>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 0.513 in 209,594 control chromosomes in the GnomAD database, including 28,930 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 (19382 hom., cov: 31)
  • Exomes 𝑓: 0.56 (9548 hom.)
• Consequence: KRAS NM_004985.5 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.682
• Publications: 19 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 12-25206009-T-C is Benign according to our data. Variant chr12-25206009-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 308065.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.78 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KRAS	NM_004985.5	c.*3786A>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.*3786A>G		3_prime_UTR_variant	Exon 5 of 5	1	NM_004985.5	ENSP00000308495.3

Frequencies

GnomAD3 genomes AF: 0.493 AC: 74797 AN: 151598 Hom.: 19371 Cov.: 31

Gnomad AFR AF: 0.329

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: 0.545

Gnomad MID AF: 0.535

Gnomad NFE AF: 0.542

Gnomad OTH AF: 0.506

GnomAD4 exome AF: 0.564 AC: 32621 AN: 57880 Hom.: 9548 Cov.: 0 AF XY: 0.567 AC XY: 15203 AN XY: 26818

African (AFR) AF: 0.328 AC: 919 AN: 2804

American (AMR) AF: 0.492 AC: 827 AN: 1682

Ashkenazi Jewish (ASJ) AF: 0.636 AC: 2358 AN: 3710

East Asian (EAS) AF: 0.782 AC: 6567 AN: 8402

South Asian (SAS) AF: 0.661 AC: 316 AN: 478

European-Finnish (FIN) AF: 0.500 AC: 19 AN: 38

Middle Eastern (MID) AF: 0.557 AC: 205 AN: 368

European-Non Finnish (NFE) AF: 0.529 AC: 18808 AN: 35560

Other (OTH) AF: 0.538 AC: 2602 AN: 4838

GnomAD4 genome AF: 0.493 AC: 74837 AN: 151714 Hom.: 19382 Cov.: 31 AF XY: 0.499 AC XY: 36985 AN XY: 74118

African (AFR) AF: 0.329 AC: 13588 AN: 41304

American (AMR) AF: 0.501 AC: 7650 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.624 AC: 2163 AN: 3466

East Asian (EAS) AF: 0.801 AC: 4136 AN: 5166

South Asian (SAS) AF: 0.668 AC: 3219 AN: 4818

European-Finnish (FIN) AF: 0.545 AC: 5719 AN: 10500

Middle Eastern (MID) AF: 0.534 AC: 157 AN: 294

European-Non Finnish (NFE) AF: 0.542 AC: 36774 AN: 67888

Other (OTH) AF: 0.507 AC: 1067 AN: 2104

Alfa AF: 0.519 Hom.: 4474

Bravo AF: 0.482

Asia WGS AF: 0.690 AC: 2388 AN: 3464

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	-0.84
CADD	Benign	7.4
DANN	Benign	0.75
PhyloP100		0.68
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs8720; hg19: chr12-25358943;