rs76660788

chr1-62535637-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.3472-5A>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 0.00341 in 1,612,494 control chromosomes in the GnomAD database, including 155 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.017 (73 hom., cov: 33)
  • Exomes 𝑓: 0.0020 (82 hom.)
• Consequence: DOCK7 NM_001367561.1 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0002429
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.0330

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=-0.78).
• BP6: Variant 1-62535637-T-C is Benign according to our data. Variant chr1-62535637-T-C is described in ClinVar as [Benign]. Clinvar id is 475137.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0573 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DOCK7	NM_001367561.1	c.3472-5A>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.3472-5A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		5	NM_001367561.1

Frequencies

GnomAD3 genomes AF: 0.0171 AC: 2601 AN: 152174 Hom.: 73 Cov.: 33

Gnomad AFR AF: 0.0592

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00609

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000353

Gnomad OTH AF: 0.0143

GnomAD3 exomes AF: 0.00481 AC: 1200 AN: 249352 Hom.: 26 AF XY: 0.00368 AC XY: 496 AN XY: 134822

Gnomad AFR exome AF: 0.0614

Gnomad AMR exome AF: 0.00410

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000547

Gnomad SAS exome AF: 0.000994

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000213

Gnomad OTH exome AF: 0.00132

GnomAD4 exome AF: 0.00198 AC: 2889 AN: 1460202 Hom.: 82 Cov.: 31 AF XY: 0.00171 AC XY: 1243 AN XY: 726376

Gnomad4 AFR exome AF: 0.0653

Gnomad4 AMR exome AF: 0.00431

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.00107

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000120

Gnomad4 OTH exome AF: 0.00458

GnomAD4 genome AF: 0.0172 AC: 2614 AN: 152292 Hom.: 73 Cov.: 33 AF XY: 0.0168 AC XY: 1251 AN XY: 74474

Gnomad4 AFR AF: 0.0593

Gnomad4 AMR AF: 0.00608

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000353

Gnomad4 OTH AF: 0.0142

Alfa AF: 0.00887 Hom.: 24

Bravo AF: 0.0200

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.000383

EpiControl AF: 0.000357

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	Jan 30, 2024	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Oct 25, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 07, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
Cadd	Benign	15
Dann	Benign	0.50
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00024
dbscSNV1_RF	Benign	0.014
SpliceAI score (max)		0.37		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.37		Position offset: 47

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs76660788; hg19: chr1-63001308;