NM_033360.4:c.*4619T>C

Variant names:

• chr12-25205297-A-G
• rs768891600
• NM_033360.4:c.*4619T>C

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Moderate BP6 BS1 BS2

The NM_033360.4(KRAS):​c.*4619T>C variant causes a 3 prime UTR change. The variant allele was found at a frequency of 0.00042 in 214,346 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). The gene KRAS is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.00032 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00066 (1 hom.)
• Consequence: KRAS NM_033360.4 3_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 5.55
• 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]

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

Specifications for KRAS are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Benign. The variant received -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.23).
• BP6: Variant 12-25205297-A-G is Benign according to our data. Variant chr12-25205297-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 308054.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000322 (49/152316) while in subpopulation AMR AF = 0.00118 (18/15300). AF 95% confidence interval is 0.00076. There are 0 homozygotes in GnomAd4. There are 21 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 49 AD gene.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRAS	NM_033360.4	MANE Plus Clinical	c.*4619T>C		3_prime_UTR	Exon 6 of 6	NP_203524.1	P01116-1
	KRAS	NM_004985.5	MANE Select	c.*4498T>C		3_prime_UTR	Exon 5 of 5	NP_004976.2
	KRAS	NM_001369786.1		c.*4619T>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.*4619T>C		3_prime_UTR	Exon 6 of 6	ENSP00000256078.5	P01116-1
	KRAS	ENST00000311936.8	TSL:1 MANE Select	c.*4498T>C		3_prime_UTR	Exon 5 of 5	ENSP00000308495.3	P01116-2
	KRAS	ENST00000685328.1		c.*4498T>C		3_prime_UTR	Exon 5 of 5	ENSP00000508921.1	P01116-2

Frequencies

GnomAD3 genomes AF: 0.000322 AC: 49 AN: 152198 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.000577

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000368

Gnomad OTH AF: 0.000478

GnomAD4 exome AF: 0.000661 AC: 41 AN: 62030 Hom.: 1 Cov.: 0 AF XY: 0.000625 AC XY: 18 AN XY: 28810

African (AFR) AF: 0.00 AC: 0 AN: 2870

American (AMR) AF: 0.00436 AC: 8 AN: 1836

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3942

East Asian (EAS) AF: 0.00 AC: 0 AN: 9084

South Asian (SAS) AF: 0.00 AC: 0 AN: 512

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 468

Middle Eastern (MID) AF: 0.00267 AC: 1 AN: 374

European-Non Finnish (NFE) AF: 0.000791 AC: 30 AN: 37918

Other (OTH) AF: 0.000398 AC: 2 AN: 5026

GnomAD4 genome AF: 0.000322 AC: 49 AN: 152316 Hom.: 0 Cov.: 33 AF XY: 0.000282 AC XY: 21 AN XY: 74480

African (AFR) AF: 0.0000722 AC: 3 AN: 41578

American (AMR) AF: 0.00118 AC: 18 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.000577 AC: 2 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000368 AC: 25 AN: 68004

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.000416 Hom.: 0

Bravo AF: 0.000578

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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	-0.23
CADD	Benign	17
DANN	Benign	0.91
PhyloP100		5.5
Mutation Taster		=99/1	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs768891600; hg19: chr12-25358231;