9-87499130-A-G

Position:

• chr9-87499130-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_004938.4(DAPK1):​c.53A>G​(p.Glu18Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: DAPK1 NM_004938.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.39

Genes affected

DAPK1 (HGNC:2674): (death associated protein kinase 1) Death-associated protein kinase 1 is a positive mediator of gamma-interferon induced programmed cell death. DAPK1 encodes a structurally unique 160-kD calmodulin dependent serine-threonine kinase that carries 8 ankyrin repeats and 2 putative P-loop consensus sites. It is a tumor suppressor candidate. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2013]

DAPK1 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), DAPK1. . Gene score misZ 2.5678 (greater than the threshold 3.09). Trascript score misZ 3.9845 (greater than threshold 3.09). GenCC has associacion of gene with autism spectrum disorder.
• BP4: Computational evidence support a benign effect (MetaRNN=0.42336577).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DAPK1	NM_004938.4	c.53A>G	p.Glu18Gly	missense_variant	2/26	ENST00000408954.8	NP_004929.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DAPK1	ENST00000408954.8	c.53A>G	p.Glu18Gly	missense_variant	2/26	2	NM_004938.4	ENSP00000386135.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000611 Hom.: 0

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

Jun 22, 2023

The c.53A>G (p.E18G) alteration is located in exon 2 (coding exon 1) of the DAPK1 gene. This alteration results from a A to G substitution at nucleotide position 53, causing the glutamic acid (E) at amino acid position 18 to be replaced by a glycine (G). 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	0.71
BayesDel_addAF	Benign	-0.024	T
BayesDel_noAF	Benign	-0.27
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.30	T;T;.;T;T;.
Eigen	Uncertain	0.68
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Pathogenic	0.97	.;.;D;.;D;.
M_CAP	Uncertain	0.099	D
MetaRNN	Benign	0.42	T;T;T;T;T;T
MetaSVM	Benign	-0.34	T
MutationAssessor	Uncertain	2.8	M;M;M;M;M;M
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-3.9	D;D;D;D;.;D
REVEL	Uncertain	0.29
Sift	Uncertain	0.0020	D;D;D;D;.;D
Sift4G	Uncertain	0.0070	D;D;D;D;D;D
Polyphen		0.99	D;D;.;D;D;.
Vest4		0.39
MutPred		0.48		Gain of catalytic residue at E18 (P = 0.0107);Gain of catalytic residue at E18 (P = 0.0107);Gain of catalytic residue at E18 (P = 0.0107);Gain of catalytic residue at E18 (P = 0.0107);Gain of catalytic residue at E18 (P = 0.0107);Gain of catalytic residue at E18 (P = 0.0107);
MVP		0.47
MPC		0.60
ClinPred		0.98	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.81
gMVP		0.53

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: chr9-90114045;