Genetic Variant NM_004985.5:c.*1083A>G (chr12-25208712-T-C) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_004985.5(KRAS):c.*1083A>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 0.187 in 232,690 control chromosomes in the GnomAD database, including 4,226 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.18 ( 2717 hom., cov: 32)

Exomes 𝑓: 0.19 ( 1509 hom. )

Consequence

KRAS
NM_004985.5 3_prime_UTR

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.00200

Variant links:

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]

KRAS links:

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]

ETFRF1 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.86).

BP6

Variant 12-25208712-T-C is Benign according to our data. Variant chr12-25208712-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 308110.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.217 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KRAS	NM_004985.5 link	c.*1083A>G		3_prime_UTR_variant	Exon 5 of 5	ENST00000311936.8	NP_004976.2	P01116-2A0A024RAV5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KRAS	ENST00000311936 link	c.*1083A>G		3_prime_UTR_variant	Exon 5 of 5	1	NM_004985.5	ENSP00000308495.3		P01116-2

Frequencies

GnomAD3 genomes

AF:

0.183

AC:

27886

AN:

152082

Hom.:

2711

Cov.:

show subpopulations

Gnomad AFR

AF:

0.134

Gnomad AMI

AF:

0.397

Gnomad AMR

AF:

0.192

Gnomad ASJ

AF:

0.169

Gnomad EAS

AF:

0.0980

Gnomad SAS

AF:

0.192

Gnomad FIN

AF:

0.150

Gnomad MID

AF:

0.231

Gnomad NFE

AF:

0.220

Gnomad OTH

AF:

0.196

GnomAD4 exome

AF:

0.193

AC:

15519

AN:

80490

Hom.:

1509

Cov.:

AF XY:

0.191

AC XY:

7088

AN XY:

37050

show subpopulations

Gnomad4 AFR exome

AF:

0.137

Gnomad4 AMR exome

AF:

0.189

Gnomad4 ASJ exome

AF:

0.155

Gnomad4 EAS exome

AF:

0.128

Gnomad4 SAS exome

AF:

0.191

Gnomad4 FIN exome

AF:

0.197

Gnomad4 NFE exome

AF:

0.217

Gnomad4 OTH exome

AF:

0.183

GnomAD4 genome

AF:

0.183

AC:

27905

AN:

152200

Hom.:

2717

Cov.:

AF XY:

0.179

AC XY:

13320

AN XY:

74410

show subpopulations

Gnomad4 AFR

AF:

0.134

Gnomad4 AMR

AF:

0.192

Gnomad4 ASJ

AF:

0.169

Gnomad4 EAS

AF:

0.0981

Gnomad4 SAS

AF:

0.193

Gnomad4 FIN

AF:

0.150

Gnomad4 NFE

AF:

0.220

Gnomad4 OTH

AF:

0.198

Alfa

AF:

0.204

Hom.:

849

Bravo

AF:

0.181

Asia WGS

AF:

0.182

AC:

631

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

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

-0.86

CADD

Benign

4.3

DANN

Benign

0.59

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over