chr3-51355615-G-A

Variant names:

• chr3-51355615-G-A
• rs4974096
• NM_004947.5:c.4250-474G>A

Variant summary

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

The NM_004947.5(DOCK3):​c.4250-474G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0676 in 152,236 control chromosomes in the GnomAD database, including 923 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 0.068 (923 hom., cov: 32)
• Consequence: DOCK3 NM_004947.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.117
• Publications: 3 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=-0.89).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.32 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004947.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DOCK3	NM_004947.5	MANE Select	c.4250-474G>A		intron	N/A	NP_004938.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DOCK3	ENST00000266037.10	TSL:1 MANE Select	c.4250-474G>A		intron	N/A	ENSP00000266037.8
	DOCK3	ENST00000945458.1		c.4076-474G>A		intron	N/A	ENSP00000615517.1
	DOCK3	ENST00000924010.1		c.3719-474G>A		intron	N/A	ENSP00000594069.1

Frequencies

GnomAD3 genomes AF: 0.0676 AC: 10290 AN: 152118 Hom.: 922 Cov.: 32

Gnomad AFR AF: 0.0745

Gnomad AMI AF: 0.109

Gnomad AMR AF: 0.220

Gnomad ASJ AF: 0.0153

Gnomad EAS AF: 0.333

Gnomad SAS AF: 0.0483

Gnomad FIN AF: 0.0289

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0189

Gnomad OTH AF: 0.0602

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

GnomAD4 genome AF: 0.0676 AC: 10294 AN: 152236 Hom.: 923 Cov.: 32 AF XY: 0.0728 AC XY: 5417 AN XY: 74430

African (AFR) AF: 0.0745 AC: 3094 AN: 41544

American (AMR) AF: 0.220 AC: 3371 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0153 AC: 53 AN: 3468

East Asian (EAS) AF: 0.333 AC: 1724 AN: 5178

South Asian (SAS) AF: 0.0483 AC: 233 AN: 4822

European-Finnish (FIN) AF: 0.0289 AC: 306 AN: 10594

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

European-Non Finnish (NFE) AF: 0.0189 AC: 1286 AN: 68018

Other (OTH) AF: 0.0591 AC: 125 AN: 2116

Alfa AF: 0.0394 Hom.: 594

Bravo AF: 0.0849

Asia WGS AF: 0.147 AC: 511 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.38
DANN	Benign	0.29
PhyloP100		-0.12
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs4974096; hg19: chr3-51393046;