12-25205894-T-G

Variant names:

• chr12-25205894-T-G
• rs12587
• NM_033360.4:c.*4022A>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004985.5(KRAS):​c.*3901A>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.516 in 215,296 control chromosomes in the GnomAD database, including 30,117 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.49 (19379 hom., cov: 31)
  • Exomes 𝑓: 0.57 (10738 hom.)
• Consequence: KRAS NM_004985.5 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 3.03
• Publications: 28 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]

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

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant 12-25205894-T-G is Benign according to our data. Variant chr12-25205894-T-G is described in ClinVar as Likely_benign. ClinVar VariationId is 308064.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.78 is higher than 0.05.

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.*4022A>C		3_prime_UTR	Exon 6 of 6	NP_203524.1	P01116-1
	KRAS	NM_004985.5	MANE Select	c.*3901A>C		3_prime_UTR	Exon 5 of 5	NP_004976.2
	KRAS	NM_001369786.1		c.*4022A>C		3_prime_UTR	Exon 6 of 6	NP_001356715.1	P01116-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRAS	ENST00000256078.10	TSL:1 MANE Plus Clinical	c.*4022A>C		3_prime_UTR	Exon 6 of 6	ENSP00000256078.5	P01116-1
	KRAS	ENST00000311936.8	TSL:1 MANE Select	c.*3901A>C		3_prime_UTR	Exon 5 of 5	ENSP00000308495.3	P01116-2
	KRAS	ENST00000685328.1		c.*3901A>C		3_prime_UTR	Exon 5 of 5	ENSP00000508921.1	P01116-2

Frequencies

GnomAD3 genomes AF: 0.493 AC: 74798 AN: 151766 Hom.: 19368 Cov.: 31

Gnomad AFR AF: 0.328

Gnomad AMI AF: 0.398

Gnomad AMR AF: 0.501

Gnomad ASJ AF: 0.624

Gnomad EAS AF: 0.800

Gnomad SAS AF: 0.669

Gnomad FIN AF: 0.544

Gnomad MID AF: 0.535

Gnomad NFE AF: 0.541

Gnomad OTH AF: 0.506

GnomAD4 exome AF: 0.571 AC: 36187 AN: 63412 Hom.: 10738 Cov.: 0 AF XY: 0.573 AC XY: 16891 AN XY: 29470

African (AFR) AF: 0.334 AC: 1025 AN: 3066

American (AMR) AF: 0.509 AC: 974 AN: 1914

Ashkenazi Jewish (ASJ) AF: 0.637 AC: 2551 AN: 4004

East Asian (EAS) AF: 0.789 AC: 7180 AN: 9096

South Asian (SAS) AF: 0.675 AC: 362 AN: 536

European-Finnish (FIN) AF: 0.542 AC: 26 AN: 48

Middle Eastern (MID) AF: 0.570 AC: 228 AN: 400

European-Non Finnish (NFE) AF: 0.536 AC: 20926 AN: 39008

Other (OTH) AF: 0.546 AC: 2915 AN: 5340

GnomAD4 genome AF: 0.493 AC: 74839 AN: 151884 Hom.: 19379 Cov.: 31 AF XY: 0.498 AC XY: 36991 AN XY: 74208

African (AFR) AF: 0.328 AC: 13604 AN: 41438

American (AMR) AF: 0.501 AC: 7637 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.624 AC: 2164 AN: 3468

East Asian (EAS) AF: 0.800 AC: 4146 AN: 5182

South Asian (SAS) AF: 0.668 AC: 3225 AN: 4828

European-Finnish (FIN) AF: 0.544 AC: 5723 AN: 10520

Middle Eastern (MID) AF: 0.534 AC: 157 AN: 294

European-Non Finnish (NFE) AF: 0.541 AC: 36756 AN: 67890

Other (OTH) AF: 0.507 AC: 1065 AN: 2102

Alfa AF: 0.509 Hom.: 3630

Bravo AF: 0.482

Asia WGS AF: 0.691 AC: 2402 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Noonan syndrome (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	13
DANN	Benign	0.74
PhyloP100		3.0
Mutation Taster		=63/37	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs12587; hg19: chr12-25358828;