17-56834796-A-T

Variant names:

• chr17-56834796-A-T
• rs1906465563
• NM_003647.3:c.1A>T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_003647.3(DGKE):​c.1A>T​(p.Met1?) variant causes a initiator codon change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: DGKE NM_003647.3 initiator_codon
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 1.22

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]

C17orf67 (HGNC:27900): (chromosome 17 open reading frame 67) Predicted to be located in extracellular region. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 10 pathogenic variants. Next in-frame start position is after 112 codons. Genomic position: 56835129. Lost 0.196 part of the original CDS.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-56834796-A-T is Pathogenic according to our data. Variant chr17-56834796-A-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 988188.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.1A>T	p.Met1?	initiator_codon_variant	Exon 2 of 12	ENST00000284061.8	NP_003638.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DGKE	ENST00000284061.8	c.1A>T	p.Met1?	initiator_codon_variant	Exon 2 of 12	1	NM_003647.3	ENSP00000284061.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Atypical hemolytic-uremic syndrome Pathogenic:1

Apr 24, 2017

Sydney Genome Diagnostics, Children's Hospital Westmead

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

This individual is homozygous for the c.1A>T variant in the DGKE gene. The variant has not been reported in any population databases (i.e. ExAC, ESP or dbSNP). To our knowledge, this variant has not been previously reported in the literature or any variant databases. This variant abolishes the translational initiation codon of the DGKE gene, and is likely to result in haploinsufficiency. This variant is considered to be likely pathogenic according to ACMG guidelines -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.034	T
BayesDel_noAF	Benign	-0.19
CADD	Uncertain	24
DANN	Benign	0.96
DEOGEN2	Benign	0.085	T;.
Eigen	Benign	-0.17
Eigen_PC	Benign	-0.050
FATHMM_MKL	Benign	0.40	N
LIST_S2	Uncertain	0.90	D;D
M_CAP	Uncertain	0.20	D
MetaRNN	Pathogenic	0.96	D;D
MetaSVM	Benign	-1.1	T
PROVEAN	Benign	-0.80	N;.
REVEL	Benign	0.21
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.054	B;.
Vest4		0.63
MutPred		0.97		Gain of stability (P = 0.2886);Gain of stability (P = 0.2886);
MVP		0.38
ClinPred		0.99	D
GERP RS		4.9
Varity_R		0.87
gMVP		0.51

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs1906465563; hg19: chr17-54912157;