17-56848105-A-G

Variant names:

• chr17-56848105-A-G
• rs1555599211
• NM_003647.3:c.888+40A>G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Moderate PP5_Moderate

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 (★).

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000017 (0 hom.)
• Consequence: DGKE NM_003647.3 intron
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 0.171
• Publications: 4 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: Likely_pathogenic. The variant received 6 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 VariationId is 548648.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.888+40A>G		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.888+40A>G		intron	N/A	ENSP00000284061.3	P52429-1
	DGKE	ENST00000572944.1	TSL:1	c.717+40A>G		intron	N/A	ENSP00000458493.1	I3L112
	DGKE	ENST00000951727.1		c.888+40A>G		intron	N/A	ENSP00000621786.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 0.00000174 AC: 2 AN: 1148968 Hom.: 0 Cov.: 16 AF XY: 0.00000177 AC XY: 1 AN XY: 565848

African (AFR) AF: 0.00 AC: 0 AN: 24582

American (AMR) AF: 0.00 AC: 0 AN: 22146

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17264

East Asian (EAS) AF: 0.00 AC: 0 AN: 30288

South Asian (SAS) AF: 0.00 AC: 0 AN: 45722

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 42654

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4138

European-Non Finnish (NFE) AF: 0.00000218 AC: 2 AN: 915556

Other (OTH) AF: 0.00 AC: 0 AN: 46618

GnomAD4 genome Cov.: 30

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Atypical hemolytic-uremic syndrome (1)
1	-	-	Hemolytic-uremic syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	21
DANN	Benign	0.82
PhyloP100		0.17
Mutation Taster		=35/65	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1555599211; hg19: chr17-54925466;