7-111728398-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001363540.2(DOCK4):c.5804C>T(p.Ser1935Leu) variant causes a missense change. The variant allele was found at a frequency of 0.035 in 1,562,028 control chromosomes in the GnomAD database, including 1,169 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.028 (88 hom., cov: 33)
  • Exomes 𝑓: 0.036 (1081 hom.)
• Consequence: DOCK4 NM_001363540.2 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 4.32

Genes affected

DOCK4 (HGNC:19192): (dedicator of cytokinesis 4) This gene is a member of the dedicator of cytokinesis (DOCK) family and encodes a protein with a DHR-1 (CZH-1) domain, a DHR-2 (CZH-2) domain and an SH3 domain. This membrane-associated, cytoplasmic protein functions as a guanine nucleotide exchange factor and is involved in regulation of adherens junctions between cells. Mutations in this gene have been associated with ovarian, prostate, glioma, and colorectal cancers. Alternatively spliced variants which encode different protein isoforms have been described, but only one has been fully characterized. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002666086).
• BP6: Variant 7-111728398-G-A is Benign according to our data. Variant chr7-111728398-G-A is described in ClinVar as [Benign]. Clinvar id is 3056048.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0277 (4214/152316) while in subpopulation NFE AF= 0.0404 (2747/68020). AF 95% confidence interval is 0.0391. There are 88 homozygotes in gnomad4. There are 2039 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd at 4218 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DOCK4	NM_001363540.2	c.5804C>T	p.Ser1935Leu	missense_variant	53/53	ENST00000428084.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DOCK4	ENST00000428084.6	c.5804C>T	p.Ser1935Leu	missense_variant	53/53	5	NM_001363540.2	P3

Frequencies

GnomAD3 genomes AF: 0.0277 AC: 4218 AN: 152198 Hom.: 88 Cov.: 33

Gnomad AFR AF: 0.00704

Gnomad AMI AF: 0.0779

Gnomad AMR AF: 0.0345

Gnomad ASJ AF: 0.0133

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00641

Gnomad FIN AF: 0.0389

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.0404

Gnomad OTH AF: 0.0378

GnomAD3 exomes AF: 0.0267 AC: 5420 AN: 202948 Hom.: 118 AF XY: 0.0275 AC XY: 2999 AN XY: 108892

Gnomad AFR exome AF: 0.00532

Gnomad AMR exome AF: 0.0182

Gnomad ASJ exome AF: 0.0185

Gnomad EAS exome AF: 0.0000578

Gnomad SAS exome AF: 0.00461

Gnomad FIN exome AF: 0.0320

Gnomad NFE exome AF: 0.0423

Gnomad OTH exome AF: 0.0318

GnomAD4 exome AF: 0.0358 AC: 50462 AN: 1409712 Hom.: 1081 Cov.: 30 AF XY: 0.0353 AC XY: 24531 AN XY: 694302

Gnomad4 AFR exome AF: 0.00420

Gnomad4 AMR exome AF: 0.0207

Gnomad4 ASJ exome AF: 0.0164

Gnomad4 EAS exome AF: 0.0000509

Gnomad4 SAS exome AF: 0.00630

Gnomad4 FIN exome AF: 0.0307

Gnomad4 NFE exome AF: 0.0416

Gnomad4 OTH exome AF: 0.0317

GnomAD4 genome AF: 0.0277 AC: 4214 AN: 152316 Hom.: 88 Cov.: 33 AF XY: 0.0274 AC XY: 2039 AN XY: 74476

Gnomad4 AFR AF: 0.00702

Gnomad4 AMR AF: 0.0343

Gnomad4 ASJ AF: 0.0133

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00621

Gnomad4 FIN AF: 0.0389

Gnomad4 NFE AF: 0.0404

Gnomad4 OTH AF: 0.0379

Alfa AF: 0.0385 Hom.: 119

Bravo AF: 0.0281

TwinsUK AF: 0.0442 AC: 164

ALSPAC AF: 0.0444 AC: 171

ESP6500AA AF: 0.00524 AC: 19

ESP6500EA AF: 0.0371 AC: 292

ExAC AF: 0.0262 AC: 3116

Asia WGS AF: 0.00606 AC: 21 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

DOCK4-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 13, 2023

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.62
Cadd	Benign	19
Dann	Benign	0.88
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.49
FATHMM_MKL	Benign	0.52	D
LIST_S2	Uncertain	0.87	D;D
MetaRNN	Benign	0.0027	T;T
MetaSVM	Benign	-0.95	T
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.71	N;N
REVEL	Benign	0.12
Sift	Benign	0.83	T;T
Sift4G	Benign	0.31	T;T
Polyphen		0.0030	.;B
Vest4		0.0090
MPC		0.058
ClinPred		0.0069	T
GERP RS		4.7
Varity_R		0.020
gMVP		0.15

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: rs34597439; hg19: chr7-111368454;