12-25205716-A-T

Variant names:

• chr12-25205716-A-T
• rs12245
• NM_004985.5:c.*4079T>A

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.*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:3
• Conservation: PhyloP100: 2.02
• Publications: 21 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=-0.82).
• BP6: Variant 12-25205716-A-T is Benign according to our data. Variant chr12-25205716-A-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId 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 rank	MANE	Protein	UniProt
KRAS	NM_004985.5	c.*4079T>A		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.*4079T>A		3_prime_UTR_variant	Exon 5 of 5	1	NM_004985.5	ENSP00000308495.3

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

African (AFR) AF: 0.335 AC: 1149 AN: 3432

American (AMR) AF: 0.498 AC: 1065 AN: 2138

Ashkenazi Jewish (ASJ) AF: 0.642 AC: 2883 AN: 4490

East Asian (EAS) AF: 0.792 AC: 7969 AN: 10062

South Asian (SAS) AF: 0.664 AC: 396 AN: 596

European-Finnish (FIN) AF: 0.500 AC: 46 AN: 92

Middle Eastern (MID) AF: 0.574 AC: 257 AN: 448

European-Non Finnish (NFE) AF: 0.543 AC: 23759 AN: 43720

Other (OTH) AF: 0.554 AC: 3285 AN: 5932

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

African (AFR) AF: 0.328 AC: 13592 AN: 41422

American (AMR) AF: 0.500 AC: 7631 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.624 AC: 2164 AN: 3468

East Asian (EAS) AF: 0.800 AC: 4138 AN: 5174

South Asian (SAS) AF: 0.668 AC: 3215 AN: 4814

European-Finnish (FIN) AF: 0.544 AC: 5717 AN: 10512

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

European-Non Finnish (NFE) AF: 0.541 AC: 36759 AN: 67894

Other (OTH) AF: 0.507 AC: 1069 AN: 2108

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:3

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

- -

Noonan syndrome and Noonan-related syndrome Benign:1

Dec 23, 2020

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: 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	-0.82
CADD	Benign	10
DANN	Benign	0.64
PhyloP100		2.0
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: rs12245; hg19: chr12-25358650;