12-25250906-T-G

Variant names:

• chr12-25250906-T-G
• rs527326817
• NM_033360.4:c.-167A>C

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS2

The NM_004985.5(KRAS):​c.-167A>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000569 in 246,040 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000063 (0 hom.)
• Consequence: KRAS NM_004985.5 5_prime_UTR
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.436
• 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 -7 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.25).
• BP6: Variant 12-25250906-T-G is Benign according to our data. Variant chr12-25250906-T-G is described in ClinVar as Likely_benign. ClinVar VariationId is 3061523.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS2: High AC in GnomAd4 at 8 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004985.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRAS	NM_033360.4	MANE Plus Clinical	c.-167A>C		5_prime_UTR	Exon 1 of 6	NP_203524.1
	KRAS	NM_004985.5	MANE Select	c.-167A>C		5_prime_UTR	Exon 1 of 5	NP_004976.2
	KRAS	NM_001369786.1		c.-154A>C		5_prime_UTR	Exon 1 of 6	NP_001356715.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRAS	ENST00000256078.10	TSL:1 MANE Plus Clinical	c.-167A>C		5_prime_UTR	Exon 1 of 6	ENSP00000256078.5
	KRAS	ENST00000311936.8	TSL:1 MANE Select	c.-167A>C		5_prime_UTR	Exon 1 of 5	ENSP00000308495.3
	KRAS	ENST00000556131.2	TSL:1	c.-167A>C		5_prime_UTR	Exon 1 of 3	ENSP00000451856.1

Frequencies

GnomAD3 genomes AF: 0.0000531 AC: 8 AN: 150592 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000245

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000888

Gnomad OTH AF: 0.000482

GnomAD4 exome AF: 0.0000629 AC: 6 AN: 95336 Hom.: 0 Cov.: 0 AF XY: 0.0000390 AC XY: 2 AN XY: 51262

African (AFR) AF: 0.000317 AC: 1 AN: 3158

American (AMR) AF: 0.00 AC: 0 AN: 2094

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 4172

East Asian (EAS) AF: 0.00 AC: 0 AN: 10614

South Asian (SAS) AF: 0.00 AC: 0 AN: 3804

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 1372

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

European-Non Finnish (NFE) AF: 0.0000635 AC: 4 AN: 63022

Other (OTH) AF: 0.000152 AC: 1 AN: 6588

GnomAD4 genome AF: 0.0000531 AC: 8 AN: 150704 Hom.: 0 Cov.: 32 AF XY: 0.0000543 AC XY: 4 AN XY: 73652

African (AFR) AF: 0.0000244 AC: 1 AN: 40966

American (AMR) AF: 0.00 AC: 0 AN: 15198

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3452

East Asian (EAS) AF: 0.00 AC: 0 AN: 5002

South Asian (SAS) AF: 0.00 AC: 0 AN: 4744

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10488

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 276

European-Non Finnish (NFE) AF: 0.0000888 AC: 6 AN: 67574

Other (OTH) AF: 0.000476 AC: 1 AN: 2100

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	KRAS-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.25
CADD	Benign	17
DANN	Benign	0.87
PhyloP100		0.44
PromoterAI		-0.038	Neutral
Mutation Taster		=231/69	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs527326817; hg19: chr12-25403840;