rs869801

chr10-127447420-G-Achr10-127447420-G-C

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 1P and 12B. PP2 BP4_Strong BA1

The NM_001290223.2(DOCK1):c.5440G>A(p.Ala1814Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.254 in 1,612,100 control chromosomes in the GnomAD database, including 53,328 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1814V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.24 (4657 hom., cov: 33)
  • Exomes 𝑓: 0.25 (48671 hom.)
• Consequence: DOCK1 NM_001290223.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.848

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]

ACMG classification

Verdict is Benign. Variant got -11 ACMG points.

• PP2: Missense variant where missense usually causes diseases, DOCK1
• BP4: Computational evidence support a benign effect (MetaRNN=0.003914416).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.261 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DOCK1	NM_001290223.2	c.5440G>A	p.Ala1814Thr	missense_variant	51/52	ENST00000623213.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DOCK1	ENST00000623213.2	c.5440G>A	p.Ala1814Thr	missense_variant	51/52	1	NM_001290223.2
DOCK1	ENST00000280333.9	c.5377G>A	p.Ala1793Thr	missense_variant	51/52	1		P1

Frequencies

GnomAD3 genomes AF: 0.242 AC: 36839 AN: 152002 Hom.: 4648 Cov.: 33

Gnomad AFR AF: 0.216

Gnomad AMI AF: 0.249

Gnomad AMR AF: 0.249

Gnomad ASJ AF: 0.320

Gnomad EAS AF: 0.118

Gnomad SAS AF: 0.240

Gnomad FIN AF: 0.232

Gnomad MID AF: 0.272

Gnomad NFE AF: 0.264

Gnomad OTH AF: 0.247

GnomAD3 exomes AF: 0.236 AC: 57962 AN: 245332 Hom.: 7141 AF XY: 0.241 AC XY: 32017 AN XY: 133050

Gnomad AFR exome AF: 0.213

Gnomad AMR exome AF: 0.196

Gnomad ASJ exome AF: 0.332

Gnomad EAS exome AF: 0.122

Gnomad SAS exome AF: 0.242

Gnomad FIN exome AF: 0.234

Gnomad NFE exome AF: 0.260

Gnomad OTH exome AF: 0.247

GnomAD4 exome AF: 0.255 AC: 372054 AN: 1459980 Hom.: 48671 Cov.: 34 AF XY: 0.256 AC XY: 186060 AN XY: 726018

Gnomad4 AFR exome AF: 0.217

Gnomad4 AMR exome AF: 0.204

Gnomad4 ASJ exome AF: 0.338

Gnomad4 EAS exome AF: 0.114

Gnomad4 SAS exome AF: 0.247

Gnomad4 FIN exome AF: 0.234

Gnomad4 NFE exome AF: 0.262

Gnomad4 OTH exome AF: 0.261

GnomAD4 genome AF: 0.242 AC: 36868 AN: 152120 Hom.: 4657 Cov.: 33 AF XY: 0.241 AC XY: 17941 AN XY: 74358

Gnomad4 AFR AF: 0.216

Gnomad4 AMR AF: 0.248

Gnomad4 ASJ AF: 0.320

Gnomad4 EAS AF: 0.118

Gnomad4 SAS AF: 0.241

Gnomad4 FIN AF: 0.232

Gnomad4 NFE AF: 0.264

Gnomad4 OTH AF: 0.245

Alfa AF: 0.259 Hom.: 11008

Bravo AF: 0.240

TwinsUK AF: 0.266 AC: 987

ALSPAC AF: 0.267 AC: 1030

ESP6500AA AF: 0.193 AC: 769

ESP6500EA AF: 0.259 AC: 2153

ExAC AF: 0.234 AC: 28235

Asia WGS AF: 0.189 AC: 661 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.80	T
BayesDel_noAF	Benign	-0.77
Cadd	Benign	0.36
Dann	Benign	0.87
DEOGEN2	Benign	0.071	T;T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.024	N
LIST_S2	Benign	0.53	T;T
MetaRNN	Benign	0.0039	T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	1.0	L;.
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.27	N;.
REVEL	Benign	0.078
Sift	Benign	0.70	T;.
Sift4G	Benign	0.50	T;T
Polyphen		0.0	B;.
Vest4		0.027
MPC		0.23
ClinPred		0.015	T
GERP RS		-10
Varity_R		0.031
gMVP		0.055

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

Other links and lift over

dbSNP: rs869801; hg19: chr10-129245684; COSMIC: COSV54730399;