9-87639461-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_004938.4(DAPK1):c.531A>G(p.Ile177Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: DAPK1 NM_004938.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.99

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, DAPK1

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DAPK1	NM_004938.4	c.531A>G	p.Ile177Met	missense_variant	5/26	ENST00000408954.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DAPK1	ENST00000408954.8	c.531A>G	p.Ile177Met	missense_variant	5/26	2	NM_004938.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

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 12, 2021

The c.531A>G (p.I177M) alteration is located in exon 5 (coding exon 4) of the DAPK1 gene. This alteration results from a A to G substitution at nucleotide position 531, causing the isoleucine (I) at amino acid position 177 to be replaced by a methionine (M). 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	0.63
BayesDel_addAF	Uncertain	0.052	T
BayesDel_noAF	Benign	-0.16
Cadd	Benign	22
Dann	Benign	0.66
DEOGEN2	Benign	0.077	T;T;.;T;T;.
Eigen	Benign	-0.14
Eigen_PC	Benign	0.027
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Benign	0.014	T
MetaRNN	Uncertain	0.64	D;D;D;D;D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	L;L;L;L;L;L
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-1.1	N;N;N;N;.;N
REVEL	Benign	0.23
Sift	Benign	0.48	T;T;T;T;.;T
Sift4G	Benign	0.50	T;T;T;T;T;T
Polyphen		0.99	D;D;.;D;D;.
Vest4		0.82
MutPred		0.53		Loss of catalytic residue at I177 (P = 0.1783);Loss of catalytic residue at I177 (P = 0.1783);Loss of catalytic residue at I177 (P = 0.1783);Loss of catalytic residue at I177 (P = 0.1783);Loss of catalytic residue at I177 (P = 0.1783);Loss of catalytic residue at I177 (P = 0.1783);
MVP		0.83
MPC		0.41
ClinPred		0.14	T
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Varity_R		0.32
gMVP		0.77

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

LitVar

Other links and lift over

dbSNP: rs1830019865; hg19: chr9-90254376;