12-25250899-T-C

Variant names:

• chr12-25250899-T-C
• rs727503111
• NM_033360.4:c.-160A>G

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4 BA1 BP7

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_033360.4 5_prime_UTR
• Clinical Significance: Benign reviewed by expert panel U:1 B:4
• Conservation: PhyloP100: -0.760
• Publications: 0 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]

KRAS Gene-Disease associations (from GenCC):

• cardiofaciocutaneous syndrome 2

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp, Ambry Genetics, PanelApp Australia
• Noonan syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• Noonan syndrome 3

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, PanelApp Australia, Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• cardiofaciocutaneous syndrome

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen
• linear nevus sebaceous syndrome

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• Costello syndrome

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_033360.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRAS	NM_033360.4	MANE Plus Clinical	c.-160A>G		5_prime_UTR	Exon 1 of 6	NP_203524.1
	KRAS	NM_004985.5	MANE Select	c.-160A>G		5_prime_UTR	Exon 1 of 5	NP_004976.2
	KRAS	NM_001369786.1		c.-147A>G		5_prime_UTR	Exon 1 of 6	NP_001356715.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRAS	ENST00000256078.10	TSL:1 MANE Plus Clinical	c.-160A>G		5_prime_UTR	Exon 1 of 6	ENSP00000256078.5
	KRAS	ENST00000311936.8	TSL:1 MANE Select	c.-160A>G		5_prime_UTR	Exon 1 of 5	ENSP00000308495.3
	KRAS	ENST00000556131.2	TSL:1	c.-160A>G		5_prime_UTR	Exon 1 of 3	ENSP00000451856.1

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

African (AFR) AF: 0.000951 AC: 3 AN: 3156

American (AMR) AF: 0.00144 AC: 3 AN: 2078

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 4144

East Asian (EAS) AF: 0.0000945 AC: 1 AN: 10580

South Asian (SAS) AF: 0.000252 AC: 1 AN: 3962

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 1418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 512

European-Non Finnish (NFE) AF: 0.000221 AC: 14 AN: 63420

Other (OTH) AF: 0.000453 AC: 3 AN: 6620

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

African (AFR) AF: 0.00344 AC: 142 AN: 41260

American (AMR) AF: 0.000788 AC: 12 AN: 15222

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3460

East Asian (EAS) AF: 0.000788 AC: 4 AN: 5074

South Asian (SAS) AF: 0.00 AC: 0 AN: 4770

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10506

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 288

European-Non Finnish (NFE) AF: 0.000192 AC: 13 AN: 67694

Other (OTH) AF: 0.000478 AC: 1 AN: 2094

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	15
DANN	Benign	0.89
PhyloP100		-0.76
PromoterAI		0.0058	Neutral
Mutation Taster		=289/11	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs727503111; hg19: chr12-25403833;