Variant 10-127023221-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The ENST00000623213.2(DOCK1):c.1349A>G(p.Tyr450Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000684 in 1,461,682 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/20 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000068 ( 0 hom. )

Consequence

DOCK1
ENST00000623213.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.25

Variant links:

Genes affected

DOCK1 (HGNC:2987): (dedicator of cytokinesis 1) This gene encodes a member of the dedicator of cytokinesis protein family. Dedicator of cytokinesis proteins act as guanine nucleotide exchange factors for small Rho family G proteins. The encoded protein regulates the small GTPase Rac, thereby influencing several biological processes, including phagocytosis and cell migration. Overexpression of this gene has also been associated with certain cancers. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2014]

DOCK1 links:

(HGNC:):

links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.97

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DOCK1	NM_001290223.2 linkuse as main transcript	c.1349A>G	p.Tyr450Cys	missense_variant	14/52	ENST00000623213.2	NP_001277152.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein
DOCK1	ENST00000623213.2 linkuse as main transcript	c.1349A>G	p.Tyr450Cys	missense_variant	14/52	1	NM_001290223.2	ENSP00000485033
	ENST00000420941.2 linkuse as main transcript	n.204+3051T>C		intron_variant, non_coding_transcript_variant		3
	ENST00000601242.5 linkuse as main transcript	n.151+3051T>C		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000201

AC:

AN:

249254

Hom.:

AF XY:

0.0000296

AC XY:

AN XY:

135228

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000354

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000684

AC:

AN:

1461682

Hom.:

Cov.:

AF XY:

0.00000963

AC XY:

AN XY:

727116

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000630

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000331

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 18, 2023

The c.1286A>G (p.Y429C) alteration is located in exon 14 (coding exon 14) of the DOCK1 gene. This alteration results from a A to G substitution at nucleotide position 1286, causing the tyrosine (Y) at amino acid position 429 to be replaced by a cysteine (C). 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

0.91

BayesDel_addAF

Pathogenic

0.20

BayesDel_noAF

Pathogenic

0.16

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.40

T;T

Eigen

Pathogenic

0.91

Eigen_PC

Pathogenic

0.82

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Pathogenic

1.0

D;D

M_CAP

Benign

0.061

MetaRNN

Pathogenic

0.97

D;D

MetaSVM

Benign

-0.53

MutationAssessor

Pathogenic

3.2

M;.

MutationTaster

Benign

1.0

PrimateAI

Pathogenic

0.85

PROVEAN

Pathogenic

-7.6

D;.

REVEL

Pathogenic

0.70

Sift

Uncertain

0.0010

D;.

Sift4G

Pathogenic

0.0010

D;D

Polyphen

0.98

D;.

Vest4

0.95

MutPred

0.85

Loss of phosphorylation at Y429 (P = 0.033);.;

MVP

0.82

MPC

0.92

ClinPred

0.99

GERP RS

5.0

Varity_R

0.78

gMVP

0.85

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over