chr10-127447420-G-A

Variant names:

• chr10-127447420-G-A
• rs869801
• NM_001290223.2:c.5440G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. 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. 15/20 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
• Publications: 30 publications found

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

Our verdict: Benign. The variant received -12 ACMG points.

• 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001290223.2. 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
	DOCK1	NM_001290223.2	MANE Select	c.5440G>A	p.Ala1814Thr	missense	Exon 51 of 52	NP_001277152.2
	DOCK1	NM_001377543.1		c.5539G>A	p.Ala1847Thr	missense	Exon 52 of 53	NP_001364472.1
	DOCK1	NM_001377544.1		c.5413G>A	p.Ala1805Thr	missense	Exon 52 of 53	NP_001364473.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DOCK1	ENST00000623213.2	TSL:1 MANE Select	c.5440G>A	p.Ala1814Thr	missense	Exon 51 of 52	ENSP00000485033.1
	DOCK1	ENST00000280333.9	TSL:1	c.5377G>A	p.Ala1793Thr	missense	Exon 51 of 52	ENSP00000280333.6

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

GnomAD2 exomes AF: 0.236 AC: 57962 AN: 245332 AF XY: 0.241

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 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

African (AFR) AF: 0.217 AC: 7269 AN: 33468

American (AMR) AF: 0.204 AC: 9054 AN: 44456

Ashkenazi Jewish (ASJ) AF: 0.338 AC: 8820 AN: 26110

East Asian (EAS) AF: 0.114 AC: 4523 AN: 39640

South Asian (SAS) AF: 0.247 AC: 21213 AN: 85932

European-Finnish (FIN) AF: 0.234 AC: 12469 AN: 53282

Middle Eastern (MID) AF: 0.306 AC: 1764 AN: 5762

European-Non Finnish (NFE) AF: 0.262 AC: 291231 AN: 1111026

Other (OTH) AF: 0.261 AC: 15711 AN: 60304

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

African (AFR) AF: 0.216 AC: 8953 AN: 41498

American (AMR) AF: 0.248 AC: 3792 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.320 AC: 1111 AN: 3472

East Asian (EAS) AF: 0.118 AC: 609 AN: 5162

South Asian (SAS) AF: 0.241 AC: 1163 AN: 4816

European-Finnish (FIN) AF: 0.232 AC: 2450 AN: 10580

Middle Eastern (MID) AF: 0.289 AC: 85 AN: 294

European-Non Finnish (NFE) AF: 0.264 AC: 17960 AN: 67994

Other (OTH) AF: 0.245 AC: 518 AN: 2116

Alfa AF: 0.256 Hom.: 20797

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 v4.9

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
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.024	N
LIST_S2	Benign	0.53	T
MetaRNN	Benign	0.0039	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	1.0	L
PhyloP100		-0.85
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.27	N
REVEL	Benign	0.078
Sift	Benign	0.70	T
Sift4G	Benign	0.50	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
Mutation Taster		=97/3	polymorphism (auto)

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

Other links and lift over

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