17-56844133-A-C

Variant names:

• chr17-56844133-A-C
• rs3760158
• NM_003647.3:c.579A>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The ENST00000284061.8(DGKE):​c.579A>C​(p.Thr193Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.729 in 1,570,546 control chromosomes in the GnomAD database, including 419,981 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. T193T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.71 (38496 hom., cov: 31)
  • Exomes 𝑓: 0.73 (381485 hom.)
• Consequence: DGKE ENST00000284061.8 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.356
• Publications: 22 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 17-56844133-A-C is Benign according to our data. Variant chr17-56844133-A-C is described in ClinVar as Benign. ClinVar VariationId is 259116.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.356 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.888 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000284061.8. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DGKE	NM_003647.3	MANE Select	c.579A>C	p.Thr193Thr	synonymous	Exon 3 of 12	NP_003638.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DGKE	ENST00000284061.8	TSL:1 MANE Select	c.579A>C	p.Thr193Thr	synonymous	Exon 3 of 12	ENSP00000284061.3
	DGKE	ENST00000572944.1	TSL:1	c.408A>C	p.Thr136Thr	synonymous	Exon 2 of 10	ENSP00000458493.1
	DGKE	ENST00000576869.5	TSL:1	n.727A>C		non_coding_transcript_exon	Exon 3 of 6

Frequencies

GnomAD3 genomes AF: 0.708 AC: 107508 AN: 151854 Hom.: 38486 Cov.: 31

Gnomad AFR AF: 0.618

Gnomad AMI AF: 0.730

Gnomad AMR AF: 0.799

Gnomad ASJ AF: 0.730

Gnomad EAS AF: 0.910

Gnomad SAS AF: 0.607

Gnomad FIN AF: 0.686

Gnomad MID AF: 0.775

Gnomad NFE AF: 0.735

Gnomad OTH AF: 0.723

GnomAD2 exomes AF: 0.726 AC: 156530 AN: 215610 AF XY: 0.721

Gnomad AFR exome AF: 0.604

Gnomad AMR exome AF: 0.824

Gnomad ASJ exome AF: 0.739

Gnomad EAS exome AF: 0.919

Gnomad FIN exome AF: 0.682

Gnomad NFE exome AF: 0.728

Gnomad OTH exome AF: 0.733

GnomAD4 exome AF: 0.731 AC: 1037347 AN: 1418574 Hom.: 381485 Cov.: 31 AF XY: 0.728 AC XY: 513891 AN XY: 705420

African (AFR) AF: 0.610 AC: 18709 AN: 30652

American (AMR) AF: 0.818 AC: 28626 AN: 34974

Ashkenazi Jewish (ASJ) AF: 0.736 AC: 18480 AN: 25102

East Asian (EAS) AF: 0.879 AC: 32915 AN: 37448

South Asian (SAS) AF: 0.607 AC: 47908 AN: 78984

European-Finnish (FIN) AF: 0.677 AC: 35870 AN: 52994

Middle Eastern (MID) AF: 0.746 AC: 4216 AN: 5652

European-Non Finnish (NFE) AF: 0.738 AC: 807536 AN: 1094090

Other (OTH) AF: 0.734 AC: 43087 AN: 58678

GnomAD4 genome AF: 0.708 AC: 107564 AN: 151972 Hom.: 38496 Cov.: 31 AF XY: 0.709 AC XY: 52618 AN XY: 74214

African (AFR) AF: 0.618 AC: 25599 AN: 41424

American (AMR) AF: 0.799 AC: 12206 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.730 AC: 2533 AN: 3470

East Asian (EAS) AF: 0.910 AC: 4713 AN: 5180

South Asian (SAS) AF: 0.605 AC: 2914 AN: 4814

European-Finnish (FIN) AF: 0.686 AC: 7223 AN: 10532

Middle Eastern (MID) AF: 0.776 AC: 228 AN: 294

European-Non Finnish (NFE) AF: 0.735 AC: 49974 AN: 67962

Other (OTH) AF: 0.717 AC: 1511 AN: 2108

Alfa AF: 0.726 Hom.: 55836

Bravo AF: 0.717

Asia WGS AF: 0.746 AC: 2592 AN: 3476

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	not provided (3)
-	-	1	Immunoglobulin-mediated membranoproliferative glomerulonephritis (1)
-	-	1	Mesangiocapillary glomerulonephritis;C3554330:Immunoglobulin-mediated membranoproliferative glomerulonephritis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	3.1
DANN	Benign	0.59
PhyloP100		-0.36
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs3760158; hg19: chr17-54921494; COSMIC: COSV52349906;