rs758712631
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP2BP4
The NM_001367561.1(DOCK7):c.3246G>T(p.Leu1082Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000144 in 1,461,638 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: not found (cov: 32)
Exomes 𝑓: 0.000014 ( 0 hom. )
Consequence
DOCK7
NM_001367561.1 missense
NM_001367561.1 missense
Scores
7
11
Clinical Significance
Conservation
PhyloP100: 0.422
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]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 2 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP2
?
Missense variant where missense usually causes diseases, DOCK7
BP4
?
Computational evidence support a benign effect (MetaRNN=0.3141352).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DOCK7 | NM_001367561.1 | c.3246G>T | p.Leu1082Phe | missense_variant | 27/50 | ENST00000635253.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DOCK7 | ENST00000635253.2 | c.3246G>T | p.Leu1082Phe | missense_variant | 27/50 | 5 | NM_001367561.1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD3 exomes AF: 0.0000120 AC: 3AN: 250896Hom.: 0 AF XY: 0.0000148 AC XY: 2AN XY: 135588
GnomAD3 exomes
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135588
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GnomAD4 exome AF: 0.0000144 AC: 21AN: 1461638Hom.: 0 Cov.: 31 AF XY: 0.0000206 AC XY: 15AN XY: 727110
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GnomAD4 genome ? Cov.: 32
GnomAD4 genome
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Cov.:
32
ExAC
?
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2
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Developmental and epileptic encephalopathy, 23 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Apr 11, 2023 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Sep 26, 2021 | In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This sequence change replaces leucine with phenylalanine at codon 1082 of the DOCK7 protein (p.Leu1082Phe). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and phenylalanine. This variant is present in population databases (rs758712631, ExAC 0.003%). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 434958). This variant has not been reported in the literature in individuals affected with DOCK7-related conditions. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Dec 07, 2016 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Uncertain
CADD
Benign
DANN
Uncertain
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D;D;D;D;D
M_CAP
Benign
T
MetaRNN
Benign
T;T;T;T;T;T;T
MetaSVM
Benign
T
MutationAssessor
Benign
L;L;.;.;.;.;L
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;.;D;.;.;.;.
REVEL
Benign
Sift
Benign
T;.;T;.;.;.;.
Sift4G
Benign
T;T;T;.;T;T;T
Polyphen
P;D;D;.;P;D;.
Vest4
MutPred
Gain of catalytic residue at L1082 (P = 0.1181);Gain of catalytic residue at L1082 (P = 0.1181);.;.;.;.;Gain of catalytic residue at L1082 (P = 0.1181);
MVP
MPC
0.52
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at