chr9-87639461-A-G

Position:

• chr9-87639461-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 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DAPK1	NM_004938.4	c.531A>G	p.Ile177Met	missense_variant	5/26	ENST00000408954.8	NP_004929.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DAPK1	ENST00000408954.8	c.531A>G	p.Ile177Met	missense_variant	5/26	2	NM_004938.4	ENSP00000386135	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
LIST_S2	Uncertain	0.95	.;.;D;.;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;