12-25205488-C-CAA

Variant names:

• chr12-25205488-C-CAA
• rs61764373
• NM_033360.4:c.*4426_*4427dupTT

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 1P and 10B. PP3 BP6_Moderate BA1

The NM_004985.5(KRAS):​c.*4305_*4306dupTT variant causes a 3 prime UTR change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0312 in 216,404 control chromosomes in the GnomAD database, including 445 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.040 (406 hom., cov: 32)
  • Exomes 𝑓: 0.010 (39 hom.)
• Consequence: KRAS NM_004985.5 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 8.64
• Publications: 4 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 -9 ACMG points.

• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• BP6: Variant 12-25205488-C-CAA is Benign according to our data. Variant chr12-25205488-C-CAA is described in ClinVar as Likely_benign. ClinVar VariationId is 308058.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.13 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.*4426_*4427dupTT		3_prime_UTR	Exon 6 of 6	NP_203524.1	P01116-1
	KRAS	NM_004985.5	MANE Select	c.*4305_*4306dupTT		3_prime_UTR	Exon 5 of 5	NP_004976.2
	KRAS	NM_001369786.1		c.*4426_*4427dupTT		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.*4426_*4427dupTT		3_prime_UTR	Exon 6 of 6	ENSP00000256078.5	P01116-1
	KRAS	ENST00000311936.8	TSL:1 MANE Select	c.*4305_*4306dupTT		3_prime_UTR	Exon 5 of 5	ENSP00000308495.3	P01116-2
	KRAS	ENST00000685328.1		c.*4305_*4306dupTT		3_prime_UTR	Exon 5 of 5	ENSP00000508921.1	P01116-2

Frequencies

GnomAD3 genomes AF: 0.0403 AC: 6118 AN: 151982 Hom.: 408 Cov.: 32

Gnomad AFR AF: 0.134

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0235

Gnomad ASJ AF: 0.00260

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.00196

Gnomad OTH AF: 0.0344

GnomAD4 exome AF: 0.00998 AC: 642 AN: 64304 Hom.: 39 Cov.: 0 AF XY: 0.00986 AC XY: 293 AN XY: 29724

African (AFR) AF: 0.120 AC: 350 AN: 2928

American (AMR) AF: 0.0258 AC: 49 AN: 1900

Ashkenazi Jewish (ASJ) AF: 0.00122 AC: 5 AN: 4108

East Asian (EAS) AF: 0.00 AC: 0 AN: 9306

South Asian (SAS) AF: 0.00 AC: 0 AN: 542

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 472

Middle Eastern (MID) AF: 0.0281 AC: 11 AN: 392

European-Non Finnish (NFE) AF: 0.00293 AC: 115 AN: 39286

Other (OTH) AF: 0.0209 AC: 112 AN: 5370

GnomAD4 genome AF: 0.0402 AC: 6118 AN: 152100 Hom.: 406 Cov.: 32 AF XY: 0.0384 AC XY: 2854 AN XY: 74366

African (AFR) AF: 0.133 AC: 5528 AN: 41456

American (AMR) AF: 0.0234 AC: 358 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00260 AC: 9 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10570

Middle Eastern (MID) AF: 0.0408 AC: 12 AN: 294

European-Non Finnish (NFE) AF: 0.00196 AC: 133 AN: 67982

Other (OTH) AF: 0.0341 AC: 72 AN: 2112

Alfa AF: 0.0339 Hom.: 33

Bravo AF: 0.0467

Asia WGS AF: 0.00693 AC: 24 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Noonan syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		8.6
Mutation Taster		=82/18	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs61764373; hg19: chr12-25358422;