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 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

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 Pathogenic (★). 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 12 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 CliVar as Pathogenic. Clinvar id is 135639.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-56844039-C-CA is described in CliVar as Pathogenic. Clinvar id is 135639.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-56844039-C-CA is described in CliVar as Pathogenic. Clinvar id is 135639.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-56844039-C-CA is described in CliVar as Pathogenic. Clinvar id is 135639.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-56844039-C-CA is described in CliVar as Pathogenic. Clinvar id is 135639.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-56844039-C-CA is described in CliVar as Pathogenic. Clinvar id is 135639.Status of the report is criteria_provided_single_submitter, 1 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;