NM_033360.4:c.112-8874T>C

Variant names:

• chr12-25236286-A-G
• rs17388587
• NM_033360.4:c.112-8874T>C

Variant summary

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

The NM_033360.4(KRAS):​c.112-8874T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.05 in 152,280 control chromosomes in the GnomAD database, including 275 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 0.050 (275 hom., cov: 31)
• Consequence: KRAS NM_033360.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.386
• Publications: 14 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=-0.89).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.097 is higher than 0.05.

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.112-8874T>C		intron	N/A	NP_203524.1
	KRAS	NM_004985.5	MANE Select	c.112-8874T>C		intron	N/A	NP_004976.2
	KRAS	NM_001369786.1		c.112-8874T>C		intron	N/A	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.112-8874T>C		intron	N/A	ENSP00000256078.5
	KRAS	ENST00000311936.8	TSL:1 MANE Select	c.112-8874T>C		intron	N/A	ENSP00000308495.3
	KRAS	ENST00000556131.2	TSL:1	c.112-1060T>C		intron	N/A	ENSP00000451856.1

Frequencies

GnomAD3 genomes AF: 0.0499 AC: 7596 AN: 152162 Hom.: 270 Cov.: 31

Gnomad AFR AF: 0.0134

Gnomad AMI AF: 0.0296

Gnomad AMR AF: 0.0878

Gnomad ASJ AF: 0.0346

Gnomad EAS AF: 0.104

Gnomad SAS AF: 0.0794

Gnomad FIN AF: 0.0320

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.0613

Gnomad OTH AF: 0.0521

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

GnomAD4 genome AF: 0.0500 AC: 7611 AN: 152280 Hom.: 275 Cov.: 31 AF XY: 0.0506 AC XY: 3766 AN XY: 74464

African (AFR) AF: 0.0134 AC: 556 AN: 41558

American (AMR) AF: 0.0878 AC: 1342 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0346 AC: 120 AN: 3470

East Asian (EAS) AF: 0.104 AC: 541 AN: 5188

South Asian (SAS) AF: 0.0799 AC: 386 AN: 4830

European-Finnish (FIN) AF: 0.0320 AC: 339 AN: 10608

Middle Eastern (MID) AF: 0.0442 AC: 13 AN: 294

European-Non Finnish (NFE) AF: 0.0613 AC: 4166 AN: 68014

Other (OTH) AF: 0.0572 AC: 121 AN: 2114

Alfa AF: 0.0598 Hom.: 197

Bravo AF: 0.0512

Asia WGS AF: 0.116 AC: 404 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	6.7
DANN	Benign	0.69
PhyloP100		0.39
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: rs17388587; hg19: chr12-25389220;