rs201785444

chr1-62625392-C-Gchr1-62625392-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_001367561.1(DOCK7):c.1292G>C(p.Gly431Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000145 in 1,589,528 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. G431G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00017 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00014 (0 hom.)
• Consequence: DOCK7 NM_001367561.1 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 7.41

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, DOCK7
• BP4: Computational evidence support a benign effect (MetaRNN=0.3950643).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DOCK7	NM_001367561.1	c.1292G>C	p.Gly431Ala	missense_variant	12/50	ENST00000635253.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DOCK7	ENST00000635253.2	c.1292G>C	p.Gly431Ala	missense_variant	12/50	5	NM_001367561.1

Frequencies

GnomAD3 genomes AF: 0.000171 AC: 26 AN: 152040 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000851

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.000960

GnomAD3 exomes AF: 0.0000814 AC: 19 AN: 233282 Hom.: 0 AF XY: 0.0000712 AC XY: 9 AN XY: 126338

Gnomad AFR exome AF: 0.000126

Gnomad AMR exome AF: 0.000207

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000375

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000827

Gnomad OTH exome AF: 0.000177

GnomAD4 exome AF: 0.000142 AC: 204 AN: 1437488 Hom.: 0 Cov.: 31 AF XY: 0.000130 AC XY: 93 AN XY: 714430

Gnomad4 AFR exome AF: 0.0000931

Gnomad4 AMR exome AF: 0.000281

Gnomad4 ASJ exome AF: 0.0000401

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000161

Gnomad4 OTH exome AF: 0.000169

GnomAD4 genome AF: 0.000171 AC: 26 AN: 152040 Hom.: 0 Cov.: 32 AF XY: 0.000189 AC XY: 14 AN XY: 74250

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.000851

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.000960

Alfa AF: 0.0000869 Hom.: 0

Bravo AF: 0.000238

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000412 AC: 5

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Developmental and epileptic encephalopathy, 23 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Sep 07, 2022	This sequence change replaces glycine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 431 of the DOCK7 protein (p.Gly431Ala). This variant is present in population databases (rs201785444, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with DOCK7-related conditions. ClinVar contains an entry for this variant (Variation ID: 578368). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 12, 2024

The c.1292G>C (p.G431A) alteration is located in exon 12 (coding exon 12) of the DOCK7 gene. This alteration results from a G to C substitution at nucleotide position 1292, causing the glycine (G) at amino acid position 431 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Feb 05, 2023

In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Benign	-0.095	T
BayesDel_noAF	Benign	-0.090
Cadd	Uncertain	25
Dann	Uncertain	0.99
Eigen	Uncertain	0.20
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D;D;D;D;D;D;D
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.40	T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.0	M;M;M;M;M;M;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-1.1	N;.;N;.;.;.;N
REVEL	Benign	0.25
Sift	Benign	0.073	T;.;T;.;.;.;T
Sift4G	Benign	0.30	T;T;T;T;T;T;T
Polyphen		0.36, 0.52, 0.55	.;B;B;P;P;.;.
Vest4		0.81
MVP		0.71
MPC		0.43
ClinPred		0.087	T
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.29
gMVP		0.54

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: rs201785444; hg19: chr1-63091063;