chr1-62648297-T-C

Position:

• chr1-62648297-T-C

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

The NM_001367561.1(DOCK7):​c.541A>G​(p.Met181Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0103 in 1,611,734 control chromosomes in the GnomAD database, including 908 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M181L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.039 (346 hom., cov: 32)
  • Exomes 𝑓: 0.0074 (562 hom.)
• Consequence: DOCK7 NM_001367561.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.29

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 -19 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), DOCK7. . Gene score misZ 3.4194 (greater than the threshold 3.09). Trascript score misZ 3.8677 (greater than threshold 3.09). GenCC has associacion of gene with developmental and epileptic encephalopathy, 23, developmental and epileptic encephalopathy.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0019033551).
• BP6: Variant 1-62648297-T-C is Benign according to our data. Variant chr1-62648297-T-C is described in ClinVar as [Benign]. Clinvar id is 447277.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.115 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DOCK7	NM_001367561.1	c.541A>G	p.Met181Val	missense_variant	6/50	ENST00000635253.2	NP_001354490.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DOCK7	ENST00000635253.2	c.541A>G	p.Met181Val	missense_variant	6/50	5	NM_001367561.1	ENSP00000489124.1

Frequencies

GnomAD3 genomes AF: 0.0385 AC: 5861 AN: 152076 Hom.: 347 Cov.: 32

Gnomad AFR AF: 0.118

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0132

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.122

Gnomad SAS AF: 0.00765

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000603

Gnomad OTH AF: 0.0297

GnomAD3 exomes AF: 0.0183 AC: 4566 AN: 249086 Hom.: 266 AF XY: 0.0154 AC XY: 2088 AN XY: 135190

Gnomad AFR exome AF: 0.120

Gnomad AMR exome AF: 0.00473

Gnomad ASJ exome AF: 0.00340

Gnomad EAS exome AF: 0.120

Gnomad SAS exome AF: 0.00511

Gnomad FIN exome AF: 0.0000463

Gnomad NFE exome AF: 0.000826

Gnomad OTH exome AF: 0.00827

GnomAD4 exome AF: 0.00741 AC: 10814 AN: 1459540 Hom.: 562 Cov.: 32 AF XY: 0.00695 AC XY: 5047 AN XY: 726046

Gnomad4 AFR exome AF: 0.117

Gnomad4 AMR exome AF: 0.00569

Gnomad4 ASJ exome AF: 0.00315

Gnomad4 EAS exome AF: 0.121

Gnomad4 SAS exome AF: 0.00519

Gnomad4 FIN exome AF: 0.0000751

Gnomad4 NFE exome AF: 0.000456

Gnomad4 OTH exome AF: 0.0129

GnomAD4 genome AF: 0.0385 AC: 5862 AN: 152194 Hom.: 346 Cov.: 32 AF XY: 0.0384 AC XY: 2856 AN XY: 74440

Gnomad4 AFR AF: 0.118

Gnomad4 AMR AF: 0.0132

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.121

Gnomad4 SAS AF: 0.00766

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000603

Gnomad4 OTH AF: 0.0294

Alfa AF: 0.00846 Hom.: 64

Bravo AF: 0.0438

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.110 AC: 484

ESP6500EA AF: 0.000931 AC: 8

ExAC AF: 0.0208 AC: 2525

Asia WGS AF: 0.0540 AC: 188 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Developmental and epileptic encephalopathy, 23 Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 18, 2021	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Jun 29, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	11
DANN	Benign	0.77
DEOGEN2	Benign	0.084	.;.;.;.;.;T;.
Eigen	Benign	-0.73
Eigen_PC	Benign	-0.52
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.62	T;T;T;T;T;T;T
MetaRNN	Benign	0.0019	T;T;T;T;T;T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	-1.1	N;N;N;N;N;N;N
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	0.24	N;.;N;.;.;.;N
REVEL	Benign	0.14
Sift	Benign	0.71	T;.;T;.;.;.;T
Sift4G	Benign	0.66	T;T;T;T;T;T;T
Polyphen		0.0, 0.0010	.;B;B;B;B;.;.
Vest4		0.095
MPC		0.39
ClinPred		0.00074	T
GERP RS		0.82
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.28
gMVP		0.41

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: rs61743961; hg19: chr1-63113968; COSMIC: COSV51999805; COSMIC: COSV51999805;