3-50933990-A-C

Position:

• chr3-50933990-A-C

Variant summary

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

The NM_004947.5(DOCK3):​c.228A>C​(p.Glu76Asp) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: DOCK3 NM_004947.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.78

Genes affected

DOCK3 (HGNC:2989): (dedicator of cytokinesis 3) This gene is specifically expressed in the central nervous system (CNS). It encodes a member of the DOCK (dedicator of cytokinesis) family of guanine nucleotide exchange factors (GEFs). This protein, dedicator of cytokinesis 3 (DOCK3), is also known as modifier of cell adhesion (MOCA) and presenilin-binding protein (PBP). The DOCK3 and DOCK1, -2 and -4 share several conserved amino acids in their DHR-2 (DOCK homology region 2) domains that are required for GEF activity, and bind directly to WAVE proteins [Wiskott-Aldrich syndrome protein (WASP) family Verprolin-homologous proteins] via their DHR-1 domains. The DOCK3 induces axonal outgrowth in CNS by stimulating membrane recruitment of the WAVE complex and activating the small G protein Rac1. This gene is associated with an attention deficit hyperactivity disorder-like phenotype by a complex chromosomal rearrangement. [provided by RefSeq, Aug 2010]

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), DOCK3. . Gene score misZ 3.9356 (greater than the threshold 3.09). Trascript score misZ 4.3808 (greater than threshold 3.09). GenCC has associacion of gene with syndromic intellectual disability, neurodevelopmental disorder with impaired intellectual development, hypotonia, and ataxia.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DOCK3	NM_004947.5	c.228A>C	p.Glu76Asp	missense_variant	5/53	ENST00000266037.10	NP_004938.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DOCK3	ENST00000266037.10	c.228A>C	p.Glu76Asp	missense_variant	5/53	1	NM_004947.5	ENSP00000266037.8

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 10, 2024

The c.228A>C (p.E76D) alteration is located in exon 5 (coding exon 5) of the DOCK3 gene. This alteration results from a A to C substitution at nucleotide position 228, causing the glutamic acid (E) at amino acid position 76 to be replaced by an aspartic acid (D). 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	0.95
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.060
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.24	T
Eigen	Uncertain	0.21
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.034	D
MetaRNN	Uncertain	0.64	D
MetaSVM	Benign	-0.73	T
MutationAssessor	Uncertain	2.3	M
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.21
Sift	Uncertain	0.018	D
Sift4G	Uncertain	0.018	D
Polyphen		0.17	B
Vest4		0.79
MutPred		0.53		Gain of glycosylation at T77 (P = 0.1062);
MVP		0.76
MPC		1.1
ClinPred		0.93	D
GERP RS		6.0
Varity_R		0.25
gMVP		0.41

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: chr3-50971421;