10-127024685-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2PP2BP4_Moderate

The NM_001290223.2(DOCK1):c.1453C>T(p.His485Tyr) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000481 in 1,455,894 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

DOCK1
NM_001290223.2 missense, splice_region

Scores

Splicing: ADA: 0.9565

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.64

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant where missense usually causes diseases, DOCK1

BP4

Computational evidence support a benign effect (MetaRNN=0.19910935).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DOCK1	NM_001290223.2 linkuse as main transcript	c.1453C>T	p.His485Tyr	missense_variant, splice_region_variant	15/52	ENST00000623213.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE
DOCK1	ENST00000623213.2 linkuse as main transcript	c.1453C>T	p.His485Tyr	missense_variant, splice_region_variant	15/52	1	NM_001290223.2
	ENST00000420941.2 linkuse as main transcript	n.204+1587G>A		intron_variant, non_coding_transcript_variant		3
	ENST00000601242.5 linkuse as main transcript	n.151+1587G>A		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000416

AC:

AN:

240434

Hom.:

AF XY:

0.00000769

AC XY:

AN XY:

129982

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.00000917

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000481

AC:

AN:

1455894

Hom.:

Cov.:

AF XY:

0.00000553

AC XY:

AN XY:

723372

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000118

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000541

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

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

Nov 17, 2022

The c.1390C>T (p.H464Y) alteration is located in exon 15 (coding exon 15) of the DOCK1 gene. This alteration results from a C to T substitution at nucleotide position 1390, causing the histidine (H) at amino acid position 464 to be replaced by a tyrosine (Y). 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

Benign

0.088

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.49

Cadd

Uncertain

Dann

Uncertain

0.99

DEOGEN2

Benign

0.11

T;T

Eigen

Benign

-0.17

Eigen_PC

Benign

0.046

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.92

D;D

M_CAP

Benign

0.0069

MetaRNN

Benign

0.20

T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

0.0

N;.

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.61

PROVEAN

Benign

-1.8

N;.

REVEL

Benign

0.063

Sift

Uncertain

0.022

D;.

Sift4G

Uncertain

0.021

D;D

Polyphen

0.047

B;.

Vest4

0.28

MutPred

0.41

Gain of methylation at K460 (P = 0.0629);.;

MVP

0.54

MPC

0.46

ClinPred

0.44

GERP RS

3.9

Varity_R

0.34

gMVP

0.13

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.96

dbscSNV1_RF

Benign

0.72

SpliceAI score (max)

0.030

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