Genetic Variant DGKE:c.888+40A>G (chr17-56848105-A-G) – ACMG Classification: Uncertain_significance (5 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2PP3_ModeratePP5

The NM_003647.3(DGKE):c.888+40A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000174 in 1,148,968 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

Frequency

Genomes: not found (cov: 30)

Exomes 𝑓: 0.0000017 ( 0 hom. )

Consequence

DGKE
NM_003647.3 intron

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 0.171

Publications

4 publications found

Variant links:

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]

DGKE links:

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]

TRIM25 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

PP5

Variant 17-56848105-A-G is Pathogenic according to our data. Variant chr17-56848105-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 548648.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 link	c.888+40A>G		intron_variant	Intron 5 of 11	ENST00000284061.8	NP_003638.1	P52429-1A1L4Q0

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
DGKE	ENST00000284061.8 link	c.888+40A>G	intron_variant	Intron 5 of 11	1	NM_003647.3	ENSP00000284061.3	P52429-1
DGKE	ENST00000572944.1 link	c.717+40A>G	intron_variant	Intron 4 of 9	1		ENSP00000458493.1	I3L112
TRIM25	ENST00000648772.1 link	n.*313+3838T>C	intron_variant	Intron 10 of 12			ENSP00000498158.1	A0A3B3IUA7

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000174

AC:

AN:

1148968

Hom.:

Cov.:

AF XY:

0.00000177

AC XY:

AN XY:

565848

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

24582

American (AMR)

AF:

0.00

AC:

AN:

22146

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

17264

East Asian (EAS)

AF:

0.00

AC:

AN:

30288

South Asian (SAS)

AF:

0.00

AC:

AN:

45722

European-Finnish (FIN)

AF:

0.00

AC:

AN:

42654

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4138

European-Non Finnish (NFE)

AF:

0.00000218

AC:

AN:

915556

Other (OTH)

AF:

0.00

AC:

AN:

46618

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.550

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Hemolytic-uremic syndrome

Pathogenic:1

Apr 08, 2015

Yale Center for Mendelian Genomics, Yale University

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

(source)

DANN

Benign

0.82

PhyloP100

0.17

Mutation Taster

=35/65

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.98

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.98

Position offset: -1

DS_DL_spliceai

0.68

Position offset: -40

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over