rs147972030

Variant names:

• chr17-56844157-CAAAA-C
• rs147972030
• NM_003647.3:c.607_610delAAAA

Your query was ambiguous. Multiple possible variants found:

• chr17-56844157-CAAAA-C
• chr17-56844157-CAAAA-CA
• chr17-56844157-CAAAA-CAAA
• chr17-56844157-CAAAA-CAAAAA

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.607_610delAAAA​(p.Lys203GlnfsTer6) variant causes a frameshift change. The variant allele was found at a frequency of 0.000000726 in 1,376,508 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic,low penetrance (★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.3e-7 (0 hom.)
• Consequence: DGKE NM_003647.3 frameshift
• Clinical Significance: Pathogenic, low penetrance criteria provided, single submitter P:1
• Conservation: PhyloP100: 4.55
• Publications: 1 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: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-56844157-CAAAA-C is Pathogenic according to our data. Variant chr17-56844157-CAAAA-C is described in ClinVar as Pathogenic,_low_penetrance. ClinVar VariationId is 4280361.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.607_610delAAAA	p.Lys203GlnfsTer6	frameshift	Exon 3 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.607_610delAAAA	p.Lys203GlnfsTer6	frameshift	Exon 3 of 12	ENSP00000284061.3	P52429-1
	DGKE	ENST00000572944.1	TSL:1	c.436_439delAAAA	p.Lys146fs	frameshift	Exon 2 of 10	ENSP00000458493.1	I3L112
	DGKE	ENST00000576869.5	TSL:1	n.755_758delAAAA		non_coding_transcript_exon	Exon 3 of 6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.26e-7 AC: 1 AN: 1376508 Hom.: 0 AF XY: 0.00000146 AC XY: 1 AN XY: 682840

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 28654

American (AMR) AF: 0.00 AC: 0 AN: 26702

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23174

East Asian (EAS) AF: 0.00 AC: 0 AN: 35986

South Asian (SAS) AF: 0.00 AC: 0 AN: 74680

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52202

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5308

European-Non Finnish (NFE) AF: 9.32e-7 AC: 1 AN: 1073174

Other (OTH) AF: 0.00 AC: 0 AN: 56628

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Pathogenic, low penetrance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		4.5
Mutation Taster		=1/199	disease causing (fs/PTC)

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: rs147972030; hg19: chr17-54921518;