chr1-62505813-C-T

Variant names:

• chr1-62505813-C-T
• rs746518826
• NM_001367561.1:c.4480G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001367561.1(DOCK7):​c.4480G>A​(p.Val1494Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000162 in 1,607,250 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: DOCK7 NM_001367561.1 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 7.91
• Publications: 3 publications found

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]

DOCK7 Gene-Disease associations (from GenCC):

• genetic developmental and epileptic encephalopathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• developmental and epileptic encephalopathy, 23

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet, G2P

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.36937267).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001367561.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DOCK7	NM_001367561.1	MANE Select	c.4480G>A	p.Val1494Ile	missense	Exon 36 of 50	NP_001354490.1
	DOCK7	NM_001330614.2		c.4453G>A	p.Val1485Ile	missense	Exon 36 of 50	NP_001317543.1
	DOCK7	NM_001271999.2		c.4453G>A	p.Val1485Ile	missense	Exon 36 of 49	NP_001258928.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DOCK7	ENST00000635253.2	TSL:5 MANE Select	c.4480G>A	p.Val1494Ile	missense	Exon 36 of 50	ENSP00000489124.1
	DOCK7	ENST00000454575.6	TSL:1	c.4453G>A	p.Val1485Ile	missense	Exon 36 of 49	ENSP00000413583.2
	DOCK7	ENST00000912940.1		c.4480G>A	p.Val1494Ile	missense	Exon 36 of 49	ENSP00000582999.1

Frequencies

GnomAD3 genomes AF: 0.0000527 AC: 8 AN: 151900 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000967

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.0000203 AC: 5 AN: 246136 AF XY: 0.0000225

Gnomad AFR exome AF: 0.000124

Gnomad AMR exome AF: 0.0000302

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000178

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000117 AC: 17 AN: 1455232 Hom.: 0 Cov.: 30 AF XY: 0.0000110 AC XY: 8 AN XY: 724180

African (AFR) AF: 0.000182 AC: 6 AN: 33034

American (AMR) AF: 0.0000465 AC: 2 AN: 43000

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25804

East Asian (EAS) AF: 0.00 AC: 0 AN: 39544

South Asian (SAS) AF: 0.00 AC: 0 AN: 85144

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53274

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5722

European-Non Finnish (NFE) AF: 0.00000721 AC: 8 AN: 1109692

Other (OTH) AF: 0.0000167 AC: 1 AN: 60018

GnomAD4 genome AF: 0.0000592 AC: 9 AN: 152018 Hom.: 0 Cov.: 32 AF XY: 0.000108 AC XY: 8 AN XY: 74288

African (AFR) AF: 0.000121 AC: 5 AN: 41466

American (AMR) AF: 0.000131 AC: 2 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3462

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00 AC: 0 AN: 4812

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10528

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68002

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.0000659 Hom.: 0

Bravo AF: 0.000121

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Developmental and epileptic encephalopathy, 23 (1)
-	1	-	Inborn genetic diseases (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.26
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.013	T
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.37	T
MetaSVM	Benign	-0.58	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		7.9
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-0.73	N
REVEL	Benign	0.17
Sift	Benign	0.13	T
Sift4G	Benign	0.10	T
Polyphen		0.99	D
Vest4		0.35
MVP		0.54
MPC		0.35
ClinPred		0.38	T
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.20
gMVP		0.22
Mutation Taster		=85/15	polymorphism

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

Other links and lift over

dbSNP: rs746518826; hg19: chr1-62971484; COSMIC: COSV52021964;