12-25209828-T-TTTC

Variant names:

• chr12-25209828-T-TTTC
• rs397517043
• NM_004985.5:c.531_533dupGAA

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PM4_Supporting PP3

The NM_004985.5(KRAS):​c.531_533dupGAA​(p.Lys178dup) variant causes a disruptive inframe insertion change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: KRAS NM_004985.5 disruptive_inframe_insertion
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 7.63
• Publications: 6 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: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_004985.5. Strenght limited to Supporting due to length of the change: 1aa.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRAS	NM_004985.5	MANE Select	c.531_533dupGAA	p.Lys178dup	disruptive_inframe_insertion	Exon 5 of 5	NP_004976.2
	KRAS	NM_033360.4	MANE Plus Clinical	c.*85_*87dupGAA		3_prime_UTR	Exon 6 of 6	NP_203524.1
	KRAS	NM_001369787.1		c.531_533dupGAA	p.Lys178dup	disruptive_inframe_insertion	Exon 5 of 5	NP_001356716.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRAS	ENST00000311936.8	TSL:1 MANE Select	c.531_533dupGAA	p.Lys178dup	disruptive_inframe_insertion	Exon 5 of 5	ENSP00000308495.3
	KRAS	ENST00000256078.10	TSL:1 MANE Plus Clinical	c.*85_*87dupGAA		3_prime_UTR	Exon 6 of 6	ENSP00000256078.5
	KRAS	ENST00000685328.1		c.531_533dupGAA	p.Lys178dup	disruptive_inframe_insertion	Exon 5 of 5	ENSP00000508921.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

Primary familial hypertrophic cardiomyopathy Uncertain:1

Dec 20, 2013

Blueprint Genetics

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.6

Splicing

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

Other links and lift over

dbSNP: rs397517043; hg19: chr12-25362762;