12-25250899-T-C

Variant names:

• chr12-25250899-T-C
• rs727503111
• NM_004985.5:c.-160A>G

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP7 BP4 BA1

This summary comes from the ClinGen Evidence Repository: The c.-160A>G variant in KRAS is classified as benign because it has been identified in 0.22088% (95% CI of 27/8628) of African alleles in gnomAD (BA1; https://gnomad.broadinstitute.org). This variant is not located within the splice consensus sequence and computational splice site prediction tools do not predict an impact on splicing (BP4, BP7). ACMG/AMP Criteria applied: BA1, BP4, BP7. LINK:https://erepo.genome.network/evrepo/ui/classification/CA176498/MONDO:0021060/004

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00026 (0 hom.)
• Consequence: KRAS NM_004985.5 5_prime_UTR
• Clinical Significance: Benign reviewed by expert panel U:1 B:4
• Conservation: PhyloP100: -0.760

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]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: For more information check the summary or visit ClinGen Evidence Repository.
• BP7: For more information check the summary or visit ClinGen Evidence Repository.
• BA1: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KRAS	NM_004985.5	c.-160A>G		5_prime_UTR_variant	Exon 1 of 5	ENST00000311936.8	NP_004976.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KRAS	ENST00000311936.8	c.-160A>G		5_prime_UTR_variant	Exon 1 of 5	1	NM_004985.5	ENSP00000308495.3

Frequencies

GnomAD3 genomes AF: 0.00114 AC: 172 AN: 151160 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00345

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000789

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000786

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000192

Gnomad OTH AF: 0.000483

GnomAD4 exome AF: 0.000261 AC: 25 AN: 95890 Hom.: 0 Cov.: 0 AF XY: 0.000232 AC XY: 12 AN XY: 51680

Gnomad4 AFR exome AF: 0.000951

Gnomad4 AMR exome AF: 0.00144

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000945

Gnomad4 SAS exome AF: 0.000252

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000221

Gnomad4 OTH exome AF: 0.000453

GnomAD4 genome AF: 0.00114 AC: 172 AN: 151274 Hom.: 0 Cov.: 32 AF XY: 0.00123 AC XY: 91 AN XY: 73966

Gnomad4 AFR AF: 0.00344

Gnomad4 AMR AF: 0.000788

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000788

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000192

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.0000713 Hom.: 0

Bravo AF: 0.00125

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:4

Revision: reviewed by expert panel

Submissions by phenotype

Noonan syndrome Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Sep 27, 2010

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The -160A>G variant in KRAS has not been previously reported in the literature n or been identified by our laboratory. This variant occurs in the 5' UTR of the g ene. Although mutations in 5' UTRs of genes have been shown to affect gene regul ation, no pathogenic mutations in the 5' UTR of KRAS have been reported to date. Therefore, this variant is likely benign, although we cannot rule out that it could contribute to the clinical features observed in this individual. -

KRAS-related disorder Benign:1

Mar 14, 2023

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Nov 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

KRAS: BS1 -

RASopathy Benign:1

Nov 04, 2019

ClinGen RASopathy Variant Curation Expert Panel

Significance: Benign

Review Status: reviewed by expert panel

Collection Method: curation

The c.-160A>G variant in KRAS is classified as benign because it has been identified in 0.22088% (95% CI of 27/8628) of African alleles in gnomAD (BA1; https://gnomad.broadinstitute.org). This variant is not located within the splice consensus sequence and computational splice site prediction tools do not predict an impact on splicing (BP4, BP7). ACMG/AMP Criteria applied: BA1, BP4, BP7. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	15
DANN	Benign	0.89

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs727503111; hg19: chr12-25403833;