chr3-51361872-A-T

Position:

• chr3-51361872-A-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP2 BP4_Strong BP6 BS2

The NM_004947.5(DOCK3):​c.5020A>T​(p.Met1674Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00145 in 1,613,104 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0015 (2 hom.)
• Consequence: DOCK3 NM_004947.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1 B:1
• Conservation: PhyloP100: 3.25

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 Benign. Variant got -8 ACMG points.

• 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.008375734).
• BP6: Variant 3-51361872-A-T is Benign according to our data. Variant chr3-51361872-A-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 547977.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DOCK3	NM_004947.5	c.5020A>T	p.Met1674Leu	missense_variant	48/53	ENST00000266037.10	NP_004938.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DOCK3	ENST00000266037.10	c.5020A>T	p.Met1674Leu	missense_variant	48/53	1	NM_004947.5	ENSP00000266037.8

Frequencies

GnomAD3 genomes AF: 0.00127 AC: 193 AN: 152118 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000290

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00295

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00185

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00126 AC: 309 AN: 246018 Hom.: 0 AF XY: 0.00147 AC XY: 196 AN XY: 133554

Gnomad AFR exome AF: 0.000195

Gnomad AMR exome AF: 0.00114

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00195

Gnomad FIN exome AF: 0.000373

Gnomad NFE exome AF: 0.00174

Gnomad OTH exome AF: 0.00117

GnomAD4 exome AF: 0.00147 AC: 2152 AN: 1460868 Hom.: 2 Cov.: 31 AF XY: 0.00150 AC XY: 1089 AN XY: 726684

Gnomad4 AFR exome AF: 0.000239

Gnomad4 AMR exome AF: 0.000896

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00200

Gnomad4 FIN exome AF: 0.000562

Gnomad4 NFE exome AF: 0.00161

Gnomad4 OTH exome AF: 0.00184

GnomAD4 genome AF: 0.00127 AC: 193 AN: 152236 Hom.: 0 Cov.: 33 AF XY: 0.00132 AC XY: 98 AN XY: 74442

Gnomad4 AFR AF: 0.000289

Gnomad4 AMR AF: 0.00294

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.000283

Gnomad4 NFE AF: 0.00185

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00162 Hom.: 0

Bravo AF: 0.00108

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00165 AC: 14

ExAC AF: 0.00128 AC: 155

EpiCase AF: 0.00224

EpiControl AF: 0.00154

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	May 30, 2017	- -

Neurodevelopmental disorder with impaired intellectual development, hypotonia, and ataxia Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Aug 13, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	18
DANN	Benign	0.69
DEOGEN2	Benign	0.091	T
Eigen	Benign	-0.20
Eigen_PC	Benign	0.022
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.0013	T
MetaRNN	Benign	0.0084	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.055	N
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.47	N
REVEL	Benign	0.076
Sift	Benign	1.0	T
Sift4G	Benign	0.52	T
Polyphen		0.0	B
Vest4		0.15
MutPred		0.22		Loss of MoRF binding (P = 0.0723);
MVP		0.21
MPC		0.45
ClinPred		0.034	T
GERP RS		5.3
Varity_R		0.38
gMVP		0.076

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs142515812; hg19: chr3-51399303;