12-25230879-A-G

Variant names:

• chr12-25230879-A-G
• rs17329025
• NM_004985.5:c.112-3467T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004985.5(KRAS):​c.112-3467T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.381 in 151,908 control chromosomes in the GnomAD database, including 12,957 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.38 (12957 hom., cov: 30)
• Consequence: KRAS NM_004985.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0910
• Publications: 8 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.772 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KRAS	NM_004985.5	c.112-3467T>C		intron_variant	Intron 2 of 4	ENST00000311936.8	NP_004976.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KRAS	ENST00000311936.8	c.112-3467T>C		intron_variant	Intron 2 of 4	1	NM_004985.5	ENSP00000308495.3

Frequencies

GnomAD3 genomes AF: 0.381 AC: 57874 AN: 151790 Hom.: 12955 Cov.: 30

Gnomad AFR AF: 0.152

Gnomad AMI AF: 0.377

Gnomad AMR AF: 0.442

Gnomad ASJ AF: 0.518

Gnomad EAS AF: 0.792

Gnomad SAS AF: 0.475

Gnomad FIN AF: 0.455

Gnomad MID AF: 0.449

Gnomad NFE AF: 0.450

Gnomad OTH AF: 0.401

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.381 AC: 57892 AN: 151908 Hom.: 12957 Cov.: 30 AF XY: 0.388 AC XY: 28765 AN XY: 74230

African (AFR) AF: 0.152 AC: 6313 AN: 41484

American (AMR) AF: 0.443 AC: 6753 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.518 AC: 1797 AN: 3466

East Asian (EAS) AF: 0.792 AC: 4089 AN: 5162

South Asian (SAS) AF: 0.474 AC: 2279 AN: 4808

European-Finnish (FIN) AF: 0.455 AC: 4770 AN: 10488

Middle Eastern (MID) AF: 0.456 AC: 134 AN: 294

European-Non Finnish (NFE) AF: 0.450 AC: 30564 AN: 67932

Other (OTH) AF: 0.403 AC: 850 AN: 2110

Alfa AF: 0.427 Hom.: 3559

Bravo AF: 0.372

Asia WGS AF: 0.592 AC: 2058 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	3.4
DANN	Benign	0.80
PhyloP100		-0.091
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs17329025; hg19: chr12-25383813;