NM_003647.3:c.1A>T

Variant names:

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

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.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 Pathogenic,low penetrance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: DGKE NM_003647.3 initiator_codon
• Clinical Significance: Pathogenic, low penetrance criteria provided, single submitter P:2
• Conservation: PhyloP100: 1.22
• Publications: 0 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]

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

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 17 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 Pathogenic,_low_penetrance. ClinVar VariationId is 988188.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003647.3. 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
	DGKE	NM_003647.3	MANE Select	c.1A>T	p.Met1?	initiator_codon	Exon 2 of 12	NP_003638.1	A1L4Q0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DGKE	ENST00000284061.8	TSL:1 MANE Select	c.1A>T	p.Met1?	initiator_codon	Exon 2 of 12	ENSP00000284061.3	P52429-1
	DGKE	ENST00000572810.1	TSL:1	c.1A>T	p.Met1?	initiator_codon	Exon 2 of 2	ENSP00000459295.1	P52429-2
	DGKE	ENST00000576869.5	TSL:1	n.149A>T		non_coding_transcript_exon	Exon 2 of 6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Pathogenic, low penetrance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
2	-	-	Atypical hemolytic-uremic syndrome (2)

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Uncertain	0.20	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Benign	-1.1	T
PhyloP100		1.2
PROVEAN	Benign	-0.80	N
REVEL	Benign	0.21
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.054	B
Vest4		0.63
MutPred		0.97		Gain of stability (P = 0.2886)
MVP		0.38
ClinPred		0.99	D
GERP RS		4.9
PromoterAI		-0.099	Neutral
Varity_R		0.87
gMVP		0.51
Mutation Taster		=35/165	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1906465563; hg19: chr17-54912157;