12-25205736-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_004985.5(KRAS):c.*4059A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000653 in 215,774 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 (★).

• Frequency:
  • Genomes: 𝑓 0.00065 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00065 (0 hom.)
• Consequence: KRAS NM_004985.5 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.242

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]

ETFRF1 (HGNC:27052): (electron transfer flavoprotein regulatory factor 1) Involved in respiratory electron transport chain. Located in mitochondrion. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 12-25205736-T-C is Benign according to our data. Variant chr12-25205736-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 2642795.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000654 (98/149746) while in subpopulation SAS AF= 0.00128 (6/4688). AF 95% confidence interval is 0.000819. There are 0 homozygotes in gnomad4. There are 40 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 98 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KRAS	NM_004985.5	c.*4059A>G		3_prime_UTR_variant	5/5	ENST00000311936.8
KRAS	NM_033360.4	c.*4180A>G		3_prime_UTR_variant	6/6	ENST00000256078.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KRAS	ENST00000256078.10	c.*4180A>G		3_prime_UTR_variant	6/6	1	NM_033360.4	A1
KRAS	ENST00000311936.8	c.*4059A>G		3_prime_UTR_variant	5/5	1	NM_004985.5	P4

Frequencies

GnomAD3 genomes AF: 0.000655 AC: 98 AN: 149632 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000416

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000268

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000395

Gnomad SAS AF: 0.00128

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00323

Gnomad NFE AF: 0.00101

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000651 AC: 43 AN: 66028 Hom.: 0 Cov.: 0 AF XY: 0.000822 AC XY: 25 AN XY: 30428

Gnomad4 AFR exome AF: 0.000305

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000859

Gnomad4 OTH exome AF: 0.00107

GnomAD4 genome AF: 0.000654 AC: 98 AN: 149746 Hom.: 0 Cov.: 32 AF XY: 0.000548 AC XY: 40 AN XY: 73050

Gnomad4 AFR AF: 0.000414

Gnomad4 AMR AF: 0.000268

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000396

Gnomad4 SAS AF: 0.00128

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00101

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00130 Hom.: 0

Bravo AF: 0.000635

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Dec 01, 2022

KRAS: BS1 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
Cadd	Benign	2.7
Dann	Benign	0.55

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs931270212; hg19: chr12-25358670;