12-55939459-C-A

Position:

• chr12-55939459-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001345.5(DGKA):​c.639C>A​(p.Phe213Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DGKA NM_001345.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.06

Genes affected

DGKA (HGNC:2849): (diacylglycerol kinase alpha) The protein encoded by this gene belongs to the eukaryotic diacylglycerol kinase family. It acts as a modulator that competes with protein kinase C for the second messenger diacylglycerol in intracellular signaling pathways. It also plays an important role in the resynthesis of phosphatidylinositols and phosphorylating diacylglycerol to phosphatidic acid. Several transcript variants encoding different isoforms have been identified for this gene. [provided by RefSeq, Apr 2017]

DGKA (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.781

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DGKA	NM_001345.5	c.639C>A	p.Phe213Leu	missense_variant	9/24	ENST00000331886.10	NP_001336.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DGKA	ENST00000331886.10	c.639C>A	p.Phe213Leu	missense_variant	9/24	5	NM_001345.5	ENSP00000328405.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

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

Aug 01, 2024

The c.639C>A (p.F213L) alteration is located in exon 9 (coding exon 8) of the DGKA gene. This alteration results from a C to A substitution at nucleotide position 639, causing the phenylalanine (F) at amino acid position 213 to be replaced by a leucine (L). 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
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.63	D;.;D;D
Eigen	Benign	-0.014
Eigen_PC	Benign	-0.093
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.94	.;D;D;.
M_CAP	Uncertain	0.19	D
MetaRNN	Pathogenic	0.78	D;D;D;D
MetaSVM	Uncertain	0.64	D
MutationAssessor	Benign	1.7	L;.;L;L
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-5.8	D;D;D;D
REVEL	Uncertain	0.61
Sift	Uncertain	0.015	D;D;D;D
Sift4G	Benign	0.067	T;T;T;T
Polyphen		1.0	D;P;D;D
Vest4		0.38
MutPred		0.64		Gain of catalytic residue at K211 (P = 0);.;Gain of catalytic residue at K211 (P = 0);Gain of catalytic residue at K211 (P = 0);
MVP		0.76
MPC		0.69
ClinPred		0.75	D
GERP RS		2.4
Varity_R		0.61
gMVP		0.88

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-56333243;