3-51352139-A-G

Variant names:

• chr3-51352139-A-G
• rs12487468
• NM_004947.5:c.4107+1747A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004947.5(DOCK3):​c.4107+1747A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0703 in 152,260 control chromosomes in the GnomAD database, including 947 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.070 (947 hom., cov: 32)
• Consequence: DOCK3 NM_004947.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.442
• Publications: 4 publications found

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]

DOCK3 Gene-Disease associations (from GenCC):

• neurodevelopmental disorder with impaired intellectual development, hypotonia, and ataxia

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• syndromic intellectual disability

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.322 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DOCK3	NM_004947.5	c.4107+1747A>G		intron_variant	Intron 40 of 52	ENST00000266037.10	NP_004938.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DOCK3	ENST00000266037.10	c.4107+1747A>G		intron_variant	Intron 40 of 52	1	NM_004947.5	ENSP00000266037.8

Frequencies

GnomAD3 genomes AF: 0.0704 AC: 10706 AN: 152142 Hom.: 945 Cov.: 32

Gnomad AFR AF: 0.0825

Gnomad AMI AF: 0.110

Gnomad AMR AF: 0.223

Gnomad ASJ AF: 0.0219

Gnomad EAS AF: 0.336

Gnomad SAS AF: 0.0495

Gnomad FIN AF: 0.0289

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0189

Gnomad OTH AF: 0.0587

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0703 AC: 10710 AN: 152260 Hom.: 947 Cov.: 32 AF XY: 0.0745 AC XY: 5546 AN XY: 74448

African (AFR) AF: 0.0824 AC: 3425 AN: 41542

American (AMR) AF: 0.223 AC: 3420 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0219 AC: 76 AN: 3470

East Asian (EAS) AF: 0.336 AC: 1736 AN: 5174

South Asian (SAS) AF: 0.0495 AC: 239 AN: 4828

European-Finnish (FIN) AF: 0.0289 AC: 306 AN: 10604

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0189 AC: 1283 AN: 68016

Other (OTH) AF: 0.0577 AC: 122 AN: 2116

Alfa AF: 0.0319 Hom.: 200

Bravo AF: 0.0878

Asia WGS AF: 0.150 AC: 524 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	3.9
DANN	Benign	0.86
PhyloP100		-0.44
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs12487468; hg19: chr3-51389570;