chr1-62528152-G-A

Variant names:

Germline classification Cancer classification (beta)

Variant summary

Our verdict is . The variant received -3 ACMG points: 0P and 3B. BP4_ModerateBP6

The NM_001367561.1(DOCK7):c.3935C>T (p.Thr1312Met) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.000229 (AC=368) in the gnomAD database across 1,607,520 control chromosomes, including 1 homozygote. The grpmax filtering allele frequency (95% CI) is 0.0041. In-silico predictor (REVEL) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign/Likely Benign (no review stars).

Frequency

Genomes: 𝑓 0.0011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00014 ( 1 hom. )

Consequence

DOCK7
NM_001367561.1 missense, splice_region

Scores

Splicing: ADA: 0.3526

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:8

Conservation

PhyloP100: 5.62

Publications

2 publications found

Variant links:

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, PanelApp Australia, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics

DOCK7 links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_001367561.1, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

BP4

Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Moderate).

BP6

ClinVar 0-star benign — supporting (BP6); ClinVar germline classification: Benign/Likely Benign, 0 star(s).

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DOCK7	NM_001367561.1	MANE Select	c.3935C>T	p.Thr1312Met	missense splice_region	Exon 31 of 50	NP_001354490.1	Q96N67-1
DOCK7	NM_001330614.2		c.3935C>T	p.Thr1312Met	missense splice_region	Exon 31 of 50	NP_001317543.1	Q96N67-6
DOCK7	NM_001271999.2		c.3935C>T	p.Thr1312Met	missense splice_region	Exon 31 of 49	NP_001258928.1	Q96N67-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DOCK7	ENST00000635253.2	TSL:5 MANE Select	c.3935C>T	p.Thr1312Met	missense splice_region	Exon 31 of 50	ENSP00000489124.1	Q96N67-1
DOCK7	ENST00000454575.6	TSL:1	c.3935C>T	p.Thr1312Met	missense splice_region	Exon 31 of 49	ENSP00000413583.2	Q96N67-2
DOCK7	ENST00000912940.1		c.3935C>T	p.Thr1312Met	missense splice_region	Exon 31 of 49	ENSP00000582999.1

Frequencies

GnomAD3 genomes

AF:

0.00112

AC:

171

AN:

152000

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00401

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000656

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000386

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000960

GnomAD2 exomes

AF:

0.000296

AC:

AN:

246376

AF XY:

0.000248

show subpopulations

Gnomad AFR exome

AF:

0.00390

Gnomad AMR exome

AF:

0.000180

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000268

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000136

AC:

198

AN:

1455402

Hom.:

Cov.:

AF XY:

0.000140

AC XY:

101

AN XY:

723570

show subpopulations

African (AFR)

AF:

0.00470

AC:

156

AN:

33206

American (AMR)

AF:

0.000161

AC:

AN:

43598

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25882

East Asian (EAS)

AF:

0.0000759

AC:

AN:

39522

South Asian (SAS)

AF:

0.0000118

AC:

AN:

84770

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53312

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5718

European-Non Finnish (NFE)

AF:

0.0000108

AC:

AN:

1109296

Other (OTH)

AF:

0.000316

AC:

AN:

60098

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00112

AC:

170

AN:

152118

Hom.:

Cov.:

AF XY:

0.00117

AC XY:

AN XY:

74348

show subpopulations

African (AFR)

AF:

0.00398

AC:

165

AN:

41500

American (AMR)

AF:

0.0000655

AC:

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.000387

AC:

AN:

5172

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10564

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68002

Other (OTH)

AF:

0.000950

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000446

Hom.:

Bravo

AF:

0.00134

Asia WGS

AF:

0.000289

AC:

AN:

3478

Local populations

ToMMo 61KJPN (+60KJPN MNV)

AF:

0.00

AC:

AN:

122634

WBBC (Westlake BioBank for Chinese) pilot

AF:

0.000446

AC:

AN:

8960

Hom.:

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

Developmental and epileptic encephalopathy, 23 (2)

not specified (2)

DOCK7-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.090

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.48

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.028

Eigen

Benign

-0.044

Eigen_PC

Benign

0.18

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.91

M_CAP

Benign

0.0078

MetaRNN

Benign

0.0066

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.34

PhyloP100

5.6

PrimateAI

Benign

0.42

PROVEAN

Benign

-1.9

REVEL

Benign

0.041

Sift

Benign

0.10

Sift4G

Benign

0.11

Varity_R

0.088

gMVP

0.24

Mutation Taster

=79/21

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.35

dbscSNV1_RF

Benign

0.35

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

Classification according to ACMG Germline Pathogenicity v2019

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

Local populations

ClinVar

Computational scores

Splicing

Publications

Other links and lift over