NM_003647.3:c.486dupA

Variant names:

• chr17-56844039-C-CA
• rs312262699
• NM_003647.3:c.486dupA

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_003647.3(DGKE):​c.486dupA​(p.Val163SerfsTer3) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic,risk factor (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DGKE NM_003647.3 frameshift
• Clinical Significance: Likely pathogenic; risk factor no assertion criteria provided P:1 O:1
• Conservation: PhyloP100: -0.0550
• Publications: 2 publications found

Genes affected

DGKE (HGNC:2852): (diacylglycerol kinase epsilon) Diacylglycerol kinases are thought to be involved mainly in the regeneration of phosphatidylinositol (PI) from diacylglycerol in the PI-cycle during cell signal transduction. When expressed in mammalian cells, DGK-epsilon shows specificity for arachidonyl-containing diacylglycerol. DGK-epsilon is expressed predominantly in testis. [provided by RefSeq, Jul 2008]

TRIM25 (HGNC:12932): (tripartite motif containing 25) The protein encoded by this gene is a member of the tripartite motif (TRIM) family. The TRIM motif includes three zinc-binding domains, a RING, a B-box type 1 and a B-box type 2, and a coiled-coil region. The protein is an RNA binding protein, functions as a ubiquitin E3 ligase and is involved in multiple cellular processes, including regulation of antiviral innate immunity. [provided by RefSeq, Sep 2021]

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-56844039-C-CA is Pathogenic according to our data. Variant chr17-56844039-C-CA is described in ClinVar as [Likely_pathogenic, risk_factor]. Clinvar id is 135639.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DGKE	NM_003647.3	c.486dupA	p.Val163SerfsTer3	frameshift_variant	Exon 3 of 12	ENST00000284061.8	NP_003638.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DGKE	ENST00000284061.8	c.486dupA	p.Val163SerfsTer3	frameshift_variant	Exon 3 of 12	1	NM_003647.3	ENSP00000284061.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic; risk factor

Submissions summary: Pathogenic:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Atypical hemolytic-uremic syndrome Pathogenic:1

-

Richard Lifton Laboratory, Yale University School of Medicine

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Hemolytic uremic syndrome, atypical, susceptibility to, 7 Other:1

May 01, 2013

OMIM

Significance: risk factor

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.055
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs312262699; hg19: chr17-54921400;