NM_001367561.1:c.3508A>G

Variant names:

• chr1-62535596-T-C
• rs770962486
• NM_001367561.1:c.3508A>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001367561.1(DOCK7):​c.3508A>G​(p.Ile1170Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000178 in 1,461,642 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000018 (0 hom.)
• Consequence: DOCK7 NM_001367561.1 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 6.27
• Publications: 0 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: Orphanet, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.13291025).

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.3508A>G	p.Ile1170Val	missense	Exon 29 of 50	NP_001354490.1	Q96N67-1
	DOCK7	NM_001330614.2		c.3508A>G	p.Ile1170Val	missense	Exon 29 of 50	NP_001317543.1	Q96N67-6
	DOCK7	NM_001271999.2		c.3508A>G	p.Ile1170Val	missense	Exon 29 of 49	NP_001258928.1	Q96N67-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DOCK7	ENST00000635253.2	TSL:5 MANE Select	c.3508A>G	p.Ile1170Val	missense	Exon 29 of 50	ENSP00000489124.1	Q96N67-1
	DOCK7	ENST00000454575.6	TSL:1	c.3508A>G	p.Ile1170Val	missense	Exon 29 of 49	ENSP00000413583.2	Q96N67-2
	DOCK7	ENST00000912940.1		c.3508A>G	p.Ile1170Val	missense	Exon 29 of 49	ENSP00000582999.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000797 AC: 2 AN: 250882 AF XY: 0.0000147

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000178 AC: 26 AN: 1461642 Hom.: 0 Cov.: 31 AF XY: 0.0000165 AC XY: 12 AN XY: 727114

African (AFR) AF: 0.000358 AC: 12 AN: 33480

American (AMR) AF: 0.0000447 AC: 2 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39648

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86212

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5766

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111904

Other (OTH) AF: 0.0000994 AC: 6 AN: 60384

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	Developmental and epileptic encephalopathy, 23 (2)
-	1	-	Inborn genetic diseases (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	23
DANN	Benign	0.96
DEOGEN2	Benign	0.0025	T
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.00059
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.0069	T
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.27	N
PhyloP100		6.3
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	0.11	N
REVEL	Benign	0.068
Sift	Benign	0.48	T
Sift4G	Benign	0.98	T
Polyphen		0.0	B
Vest4		0.46
MutPred		0.42		Gain of methylation at K1169 (P = 0.0547)
MVP		0.25
MPC		0.32
ClinPred		0.46	T
GERP RS		5.0
Varity_R		0.19
gMVP		0.16
Mutation Taster		=86/14	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
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

Other links and lift over

dbSNP: rs770962486; hg19: chr1-63001267;