rs143701798

chr1-62663044-T-C

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001367561.1(DOCK7):c.125A>G(p.Asn42Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000234 in 1,613,560 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0012 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00013 (0 hom.)
• Consequence: DOCK7 NM_001367561.1 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.0510

Genes affected

DOCK7 (HGNC:19190): (dedicator of cytokinesis 7) The protein encoded by this gene is a guanine nucleotide exchange factor (GEF) that plays a role in axon formation and neuronal polarization. The encoded protein displays GEF activity toward RAC1 and RAC3 Rho small GTPases but not toward CDC42. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2012]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• PP2: Missense variant where missense usually causes diseases, DOCK7
• BP4: Computational evidence support a benign effect (MetaRNN=0.0067307055).
• BP6: Variant 1-62663044-T-C is Benign according to our data. Variant chr1-62663044-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 475123.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00125 (190/152236) while in subpopulation AFR AF= 0.0039 (162/41544). AF 95% confidence interval is 0.00341. There are 2 homozygotes in gnomad4. There are 81 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DOCK7	NM_001367561.1	c.125A>G	p.Asn42Ser	missense_variant	2/50	ENST00000635253.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DOCK7	ENST00000635253.2	c.125A>G	p.Asn42Ser	missense_variant	2/50	5	NM_001367561.1

Frequencies

GnomAD3 genomes AF: 0.00124 AC: 189 AN: 152116 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00389

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00192

GnomAD3 exomes AF: 0.000314 AC: 79 AN: 251338 Hom.: 1 AF XY: 0.000265 AC XY: 36 AN XY: 135840

Gnomad AFR exome AF: 0.00357

Gnomad AMR exome AF: 0.000318

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000981

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000528

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000128 AC: 187 AN: 1461324 Hom.: 0 Cov.: 31 AF XY: 0.000114 AC XY: 83 AN XY: 726980

Gnomad4 AFR exome AF: 0.00362

Gnomad4 AMR exome AF: 0.000403

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000234

Gnomad4 OTH exome AF: 0.000315

GnomAD4 genome AF: 0.00125 AC: 190 AN: 152236 Hom.: 2 Cov.: 32 AF XY: 0.00109 AC XY: 81 AN XY: 74438

Gnomad4 AFR AF: 0.00390

Gnomad4 AMR AF: 0.00131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000416

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00190

Alfa AF: 0.000248 Hom.: 0

Bravo AF: 0.00145

ESP6500AA AF: 0.00409 AC: 18

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000428 AC: 52

EpiCase AF: 0.0000546

EpiControl AF: 0.00

ClinVar

Significance: Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Developmental and epileptic encephalopathy, 23 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Dec 31, 2023	- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Apr 07, 2021

- -

DOCK7-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 11, 2022

This variant is classified as likely 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	0.062
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.78
Cadd	Benign	5.9
Dann	Benign	0.42
Eigen	Benign	-0.85
Eigen_PC	Benign	-0.70
FATHMM_MKL	Benign	0.29	N
LIST_S2	Benign	0.84	T;T;T;T;T;T;T
M_CAP	Benign	0.0039	T
MetaRNN	Benign	0.0067	T;T;T;T;T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	-0.28	N;N;N;N;N;N;N
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.40	T
PROVEAN	Benign	0.23	N;.;N;.;.;.;N
REVEL	Benign	0.079
Sift	Benign	1.0	T;.;T;.;.;.;T
Sift4G	Benign	1.0	T;T;T;T;T;T;T
Polyphen		0.0	.;B;B;.;.;.;.
Vest4		0.10
MVP		0.19
MPC		0.31
ClinPred		0.0029	T
GERP RS		-2.3
Varity_R		0.040
gMVP		0.25

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: rs143701798; hg19: chr1-63128715;