11-46333376-A-T

Position:

• chr11-46333376-A-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_Moderate BS2_Supporting

The NM_201532.3(DGKZ):​c.101A>T​(p.Glu34Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000121 in 1,237,082 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/15 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: DGKZ NM_201532.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.685

Genes affected

DGKZ (HGNC:2857): (diacylglycerol kinase zeta) The protein encoded by this gene belongs to the eukaryotic diacylglycerol kinase family. It may attenuate protein kinase C activity by regulating diacylglycerol levels in intracellular signaling cascade and signal transduction. Alternative splicing occurs at this locus and multiple transcript variants encoding distinct isoforms have been identified. [provided by RefSeq, Nov 2010]

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.113015056).
• BS2: High AC in GnomAdExome4 at 15 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DGKZ	NM_201532.3	c.101A>T	p.Glu34Val	missense_variant	1/31		NP_963290.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DGKZ	ENST00000343674.10	c.101A>T	p.Glu34Val	missense_variant	1/31	2		ENSP00000343065.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000121 AC: 15 AN: 1237082 Hom.: 0 Cov.: 30 AF XY: 0.0000149 AC XY: 9 AN XY: 603224

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000148

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 12, 2023

The c.101A>T (p.E34V) alteration is located in exon 1 (coding exon 1) of the DGKZ gene. This alteration results from a A to T substitution at nucleotide position 101, causing the glutamic acid (E) at amino acid position 34 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	22
DANN	Benign	0.96
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.42
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.45	T
M_CAP	Benign	0.054	D
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-1.1	T
PROVEAN	Benign	-0.56	N
REVEL	Benign	0.0070
Sift	Benign	0.050	D
Sift4G	Benign	0.27	T
Vest4		0.22
MutPred		0.34		Gain of sheet (P = 0.0028);
MVP		0.43
ClinPred		0.27	T
GERP RS		3.4

Splicing

Name	Calibrated prediction	Score	Prediction
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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-46354926;