rs139793443

chr1-62633567-G-Achr1-62633567-G-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001367561.1(DOCK7):c.1047C>T(p.Val349=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00426 in 1,611,876 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. V349V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0029 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0044 (17 hom.)
• Consequence: DOCK7 NM_001367561.1 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.859

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 1-62633567-G-A is Benign according to our data. Variant chr1-62633567-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 475121.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-62633567-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.859 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00293 (446/152160) while in subpopulation NFE AF= 0.00537 (365/68012). AF 95% confidence interval is 0.00491. There are 1 homozygotes in gnomad4. There are 186 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DOCK7	NM_001367561.1	c.1047C>T	p.Val349=	synonymous_variant	10/50	ENST00000635253.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DOCK7	ENST00000635253.2	c.1047C>T	p.Val349=	synonymous_variant	10/50	5	NM_001367561.1

Frequencies

GnomAD3 genomes AF: 0.00293 AC: 446 AN: 152042 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000821

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000918

Gnomad ASJ AF: 0.00547

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000416

Gnomad FIN AF: 0.00113

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00537

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00269 AC: 671 AN: 249642 Hom.: 3 AF XY: 0.00271 AC XY: 365 AN XY: 134914

Gnomad AFR exome AF: 0.000741

Gnomad AMR exome AF: 0.000732

Gnomad ASJ exome AF: 0.00528

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000529

Gnomad FIN exome AF: 0.00139

Gnomad NFE exome AF: 0.00460

Gnomad OTH exome AF: 0.00247

GnomAD4 exome AF: 0.00440 AC: 6416 AN: 1459716 Hom.: 17 Cov.: 30 AF XY: 0.00429 AC XY: 3113 AN XY: 726160

Gnomad4 AFR exome AF: 0.000629

Gnomad4 AMR exome AF: 0.000742

Gnomad4 ASJ exome AF: 0.00648

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000617

Gnomad4 FIN exome AF: 0.00205

Gnomad4 NFE exome AF: 0.00517

Gnomad4 OTH exome AF: 0.00463

GnomAD4 genome AF: 0.00293 AC: 446 AN: 152160 Hom.: 1 Cov.: 32 AF XY: 0.00250 AC XY: 186 AN XY: 74384

Gnomad4 AFR AF: 0.000819

Gnomad4 AMR AF: 0.000917

Gnomad4 ASJ AF: 0.00547

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000416

Gnomad4 FIN AF: 0.00113

Gnomad4 NFE AF: 0.00537

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00340 Hom.: 0

Bravo AF: 0.00284

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00395

EpiControl AF: 0.00357

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 22, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2023	DOCK7: BP4, BP7, BS2 -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 05, 2019	- -

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	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
Cadd	Benign	5.5
Dann	Benign	0.57

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs139793443; hg19: chr1-63099238;