1-62494320-C-T

Variant names:

• chr1-62494320-C-T
• rs772608037
• NM_001367561.1:c.5172G>A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001367561.1(DOCK7):​c.5172G>A​(p.Met1724Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000151 in 1,454,768 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: DOCK7 NM_001367561.1 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 7.91

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DOCK7	NM_001367561.1	c.5172G>A	p.Met1724Ile	missense_variant	Exon 40 of 50	ENST00000635253.2	NP_001354490.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DOCK7	ENST00000635253.2	c.5172G>A	p.Met1724Ile	missense_variant	Exon 40 of 50	5	NM_001367561.1	ENSP00000489124.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000400 AC: 1 AN: 250088 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135168

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000882

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000151 AC: 22 AN: 1454768 Hom.: 0 Cov.: 30 AF XY: 0.0000125 AC XY: 9 AN XY: 722814

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000190

Gnomad4 OTH exome AF: 0.0000167

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000329 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Developmental and epileptic encephalopathy, 23 Uncertain:2

Apr 11, 2023

Genome-Nilou Lab

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 28, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. 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. ClinVar contains an entry for this variant (Variation ID: 574108). This variant has not been reported in the literature in individuals affected with DOCK7-related conditions. This variant is present in population databases (rs772608037, gnomAD 0.0009%). This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 1715 of the DOCK7 protein (p.Met1715Ile). -

Inborn genetic diseases Uncertain:1

Sep 27, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.5079G>A (p.M1693I) alteration is located in exon 39 (coding exon 39) of the DOCK7 gene. This alteration results from a G to A substitution at nucleotide position 5079, causing the methionine (M) at amino acid position 1693 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.030
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.097	.;.;.;T;.;.;T
Eigen	Uncertain	0.67
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;D;D;D;D;D;D
M_CAP	Benign	0.060	D
MetaRNN	Uncertain	0.57	D;D;D;D;D;D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Pathogenic	3.0	.;.;.;.;.;.;M
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-2.4	N;.;N;.;.;.;.
REVEL	Uncertain	0.39
Sift	Uncertain	0.0040	D;.;D;.;.;.;.
Sift4G	Uncertain	0.0090	D;D;D;.;D;D;D
Polyphen		0.78	P;P;B;.;P;B;P
Vest4		0.65
MutPred		0.41		.;.;.;.;.;.;Gain of ubiquitination at K1729 (P = 0.1062);
MVP		0.72
MPC		0.60
ClinPred		0.83	D
GERP RS		6.0
Varity_R		0.49
gMVP		0.63

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: rs772608037; hg19: chr1-62959991;