rs17123688

chr1-62510677-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001367561.1(DOCK7):c.4283-4A>G variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0112 in 1,610,796 control chromosomes in the GnomAD database, including 687 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.037 (254 hom., cov: 32)
  • Exomes 𝑓: 0.0085 (433 hom.)
• Consequence: DOCK7 NM_001367561.1 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.009862
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.321

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant 1-62510677-T-C is Benign according to our data. Variant chr1-62510677-T-C is described in ClinVar as [Benign]. Clinvar id is 475145.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.104 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DOCK7	NM_001367561.1	c.4283-4A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000635253.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DOCK7	ENST00000635253.2	c.4283-4A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		5	NM_001367561.1

Frequencies

GnomAD3 genomes AF: 0.0366 AC: 5569 AN: 152146 Hom.: 251 Cov.: 32

Gnomad AFR AF: 0.106

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0353

Gnomad ASJ AF: 0.00779

Gnomad EAS AF: 0.0539

Gnomad SAS AF: 0.0311

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00166

Gnomad OTH AF: 0.0277

GnomAD3 exomes AF: 0.0186 AC: 4650 AN: 249428 Hom.: 140 AF XY: 0.0167 AC XY: 2245 AN XY: 134828

Gnomad AFR exome AF: 0.108

Gnomad AMR exome AF: 0.0242

Gnomad ASJ exome AF: 0.00798

Gnomad EAS exome AF: 0.0486

Gnomad SAS exome AF: 0.0296

Gnomad FIN exome AF: 0.000370

Gnomad NFE exome AF: 0.00130

Gnomad OTH exome AF: 0.0114

GnomAD4 exome AF: 0.00854 AC: 12455 AN: 1458532 Hom.: 433 Cov.: 29 AF XY: 0.00881 AC XY: 6391 AN XY: 725602

Gnomad4 AFR exome AF: 0.114

Gnomad4 AMR exome AF: 0.0257

Gnomad4 ASJ exome AF: 0.00798

Gnomad4 EAS exome AF: 0.0627

Gnomad4 SAS exome AF: 0.0292

Gnomad4 FIN exome AF: 0.000450

Gnomad4 NFE exome AF: 0.00125

Gnomad4 OTH exome AF: 0.0141

GnomAD4 genome AF: 0.0367 AC: 5591 AN: 152264 Hom.: 254 Cov.: 32 AF XY: 0.0372 AC XY: 2766 AN XY: 74444

Gnomad4 AFR AF: 0.106

Gnomad4 AMR AF: 0.0354

Gnomad4 ASJ AF: 0.00779

Gnomad4 EAS AF: 0.0537

Gnomad4 SAS AF: 0.0313

Gnomad4 FIN AF: 0.000283

Gnomad4 NFE AF: 0.00166

Gnomad4 OTH AF: 0.0284

Alfa AF: 0.0169 Hom.: 59

Bravo AF: 0.0407

Asia WGS AF: 0.0650 AC: 224 AN: 3474

EpiCase AF: 0.00137

EpiControl AF: 0.00160

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Developmental and epileptic encephalopathy, 23 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 15, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 18, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
Cadd	Benign	9.4
Dann	Benign	0.65

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0099
dbscSNV1_RF	Benign	0.29
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

Publications

LitVar

Other links and lift over

dbSNP: rs17123688; hg19: chr1-62976348; COSMIC: COSV51999716;