NM_003647.3:c.465-3C>T

Variant names:

• chr17-56844016-C-T
• rs375726408
• NM_003647.3:c.465-3C>T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_003647.3(DGKE):​c.465-3C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000405 in 1,537,696 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00027 (3 hom.)
• Consequence: DGKE NM_003647.3 splice_region, intron
• Scores: Splicing: ADA: 0.01353
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts U:2 B:2
• Conservation: PhyloP100: 2.77
• 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]

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]

LOC124904036 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.27).
• BP6: Variant 17-56844016-C-T is Benign according to our data. Variant chr17-56844016-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 718637.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0016 (243/152168) while in subpopulation AFR AF = 0.0045 (187/41520). AF 95% confidence interval is 0.00398. There are 0 homozygotes in GnomAd4. There are 111 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 3 AR gene

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.465-3C>T		splice_region intron	N/A	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.465-3C>T		splice_region intron	N/A	ENSP00000284061.3	P52429-1
	DGKE	ENST00000572944.1	TSL:1	c.294-3C>T		splice_region intron	N/A	ENSP00000458493.1	I3L112
	DGKE	ENST00000576869.5	TSL:1	n.613-3C>T		splice_region intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00161 AC: 245 AN: 152050 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00454

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00184

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000323

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.000507 AC: 96 AN: 189310 AF XY: 0.000384

Gnomad AFR exome AF: 0.00419

Gnomad AMR exome AF: 0.00102

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000486

Gnomad NFE exome AF: 0.000245

Gnomad OTH exome AF: 0.000470

GnomAD4 exome AF: 0.000274 AC: 380 AN: 1385528 Hom.: 3 Cov.: 31 AF XY: 0.000271 AC XY: 186 AN XY: 687002

African (AFR) AF: 0.00456 AC: 130 AN: 28518

American (AMR) AF: 0.00115 AC: 31 AN: 26872

Ashkenazi Jewish (ASJ) AF: 0.0000417 AC: 1 AN: 23978

East Asian (EAS) AF: 0.00 AC: 0 AN: 34666

South Asian (SAS) AF: 0.0000135 AC: 1 AN: 73876

European-Finnish (FIN) AF: 0.0000380 AC: 2 AN: 52676

Middle Eastern (MID) AF: 0.00215 AC: 12 AN: 5574

European-Non Finnish (NFE) AF: 0.000141 AC: 153 AN: 1082136

Other (OTH) AF: 0.000874 AC: 50 AN: 57232

GnomAD4 genome AF: 0.00160 AC: 243 AN: 152168 Hom.: 0 Cov.: 32 AF XY: 0.00149 AC XY: 111 AN XY: 74364

African (AFR) AF: 0.00450 AC: 187 AN: 41520

American (AMR) AF: 0.00183 AC: 28 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10588

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.000323 AC: 22 AN: 68012

Other (OTH) AF: 0.00142 AC: 3 AN: 2106

Alfa AF: 0.000703 Hom.: 0

Bravo AF: 0.00198

Asia WGS AF: 0.000289 AC: 1 AN: 3476

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	2	not provided (4)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.27
CADD	Benign	13
DANN	Benign	0.87
PhyloP100		2.8
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.014
dbscSNV1_RF	Benign	0.038
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: rs375726408; hg19: chr17-54921377;