dbSNP rs766243416: DOCK7:p.Leu143Phe (chr1-62648505-T-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001367561.1(DOCK7):c.429A>T(p.Leu143Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000758 in 1,319,274 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Synonymous variant affecting the same amino acid position (i.e. L143L) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.6e-7 ( 0 hom. )

Consequence

DOCK7
NM_001367561.1 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.698

Publications

0 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet, G2P

DOCK7 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.16918689).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DOCK7	NM_001367561.1 link	c.429A>T	p.Leu143Phe	missense_variant	Exon 5 of 50	ENST00000635253.2	NP_001354490.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DOCK7	ENST00000635253.2 link	c.429A>T	p.Leu143Phe	missense_variant	Exon 5 of 50	5	NM_001367561.1	ENSP00000489124.1		Q96N67-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.58e-7

AC:

AN:

1319274

Hom.:

Cov.:

AF XY:

0.00000153

AC XY:

AN XY:

652906

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

28806

American (AMR)

AF:

0.00

AC:

AN:

33450

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23858

East Asian (EAS)

AF:

0.00

AC:

AN:

34296

South Asian (SAS)

AF:

0.00

AC:

AN:

67500

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48012

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3972

European-Non Finnish (NFE)

AF:

9.76e-7

AC:

AN:

1025108

Other (OTH)

AF:

0.00

AC:

AN:

54272

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.34

BayesDel_addAF

Uncertain

0.047

BayesDel_noAF

Benign

-0.17

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.21

.;.;.;.;.;T;.

Eigen

Benign

-0.26

Eigen_PC

Benign

-0.20

FATHMM_MKL

Uncertain

0.88

LIST_S2

Uncertain

0.93

D;D;D;D;D;D;D

M_CAP

Benign

0.013

MetaRNN

Benign

0.17

T;T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.7

L;L;L;L;L;L;L

PhyloP100

0.70

PrimateAI

Pathogenic

0.85

PROVEAN

Benign

-0.77

N;.;N;.;.;.;N

REVEL

Benign

0.18

Sift

Benign

0.36

T;.;T;.;.;.;T

Sift4G

Benign

0.63

T;T;T;T;T;T;T

Polyphen

0.27, 0.13, 0.0

.;B;B;B;B;.;.

Vest4

0.63

MutPred

0.27

Gain of ubiquitination at K145 (P = 0.0688);Gain of ubiquitination at K145 (P = 0.0688);Gain of ubiquitination at K145 (P = 0.0688);Gain of ubiquitination at K145 (P = 0.0688);Gain of ubiquitination at K145 (P = 0.0688);Gain of ubiquitination at K145 (P = 0.0688);Gain of ubiquitination at K145 (P = 0.0688);

MVP

0.82

MPC

0.55

ClinPred

0.59

GERP RS

2.2

Varity_R

0.18

gMVP

0.53

Mutation Taster

=53/47

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over