rs1022182913

Variant names:

• chr1-62539880-C-T
• rs1022182913
• NM_001367561.1:c.3058G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001367561.1(DOCK7):​c.3058G>A​(p.Val1020Met) variant causes a missense change. The variant allele was found at a frequency of 0.00000207 in 1,446,718 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V1020L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: DOCK7 NM_001367561.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.08
• Publications: 0 publications found

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]

DOCK7 Gene-Disease associations (from GenCC):

• genetic developmental and epileptic encephalopathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• developmental and epileptic encephalopathy, 23

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet, G2P

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.31253326).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DOCK7	NM_001367561.1	c.3058G>A	p.Val1020Met	missense_variant	Exon 26 of 50	ENST00000635253.2	NP_001354490.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DOCK7	ENST00000635253.2	c.3058G>A	p.Val1020Met	missense_variant	Exon 26 of 50	5	NM_001367561.1	ENSP00000489124.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000419 AC: 1 AN: 238756 AF XY: 0.00000777

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000315

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000207 AC: 3 AN: 1446718 Hom.: 0 Cov.: 30 AF XY: 0.00000417 AC XY: 3 AN XY: 718856

African (AFR) AF: 0.00 AC: 0 AN: 32692

American (AMR) AF: 0.0000241 AC: 1 AN: 41476

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25610

East Asian (EAS) AF: 0.00 AC: 0 AN: 39508

South Asian (SAS) AF: 0.00 AC: 0 AN: 82140

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53152

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5674

European-Non Finnish (NFE) AF: 9.04e-7 AC: 1 AN: 1106696

Other (OTH) AF: 0.0000167 AC: 1 AN: 59770

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Developmental and epileptic encephalopathy, 23 Uncertain:1

Jul 07, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 1020 of the DOCK7 protein (p.Val1020Met). 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: 541918). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt DOCK7 protein function. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.39
BayesDel_addAF	Benign	-0.059	T
BayesDel_noAF	Benign	-0.32
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.029	.;.;.;T;.;.;T
Eigen	Uncertain	0.22
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D;D;D
M_CAP	Benign	0.0091	T
MetaRNN	Benign	0.31	T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.3	L;L;.;.;.;.;L
PhyloP100		6.1
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-1.1	N;.;N;.;.;.;.
REVEL	Benign	0.12
Sift	Uncertain	0.021	D;.;D;.;.;.;.
Sift4G	Uncertain	0.037	D;D;D;.;D;D;D
Polyphen		0.31	B;P;B;.;B;B;.
Vest4		0.44
MutPred		0.46		Loss of ubiquitination at K1017 (P = 0.1037);Loss of ubiquitination at K1017 (P = 0.1037);.;.;.;.;Loss of ubiquitination at K1017 (P = 0.1037);
MVP		0.38
MPC		0.40
ClinPred		0.79	D
GERP RS		5.2
Varity_R		0.14
gMVP		0.42
Mutation Taster		=89/11	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1022182913; hg19: chr1-63005551;