rs778470902
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Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP2BP4
The NM_001367561.1(DOCK7):āc.2516A>Gā(p.His839Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000118 in 1,613,862 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 (ā ā ).
Frequency
Genomes: š 0.0000066 ( 0 hom., cov: 32)
Exomes š: 0.000012 ( 0 hom. )
Consequence
DOCK7
NM_001367561.1 missense
NM_001367561.1 missense
Scores
1
7
11
Clinical Significance
Conservation
PhyloP100: 8.02
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 in gene, where missense usually causes diseases (based on misZ statistic), DOCK7. . Gene score misZ 3.4194 (greater than the threshold 3.09). Trascript score misZ 3.8677 (greater than threshold 3.09). GenCC has associacion of gene with developmental and epileptic encephalopathy, 23, developmental and epileptic encephalopathy.
BP4
Computational evidence support a benign effect (MetaRNN=0.29079515).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
DOCK7 | NM_001367561.1 | c.2516A>G | p.His839Arg | missense_variant | 21/50 | ENST00000635253.2 | NP_001354490.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
DOCK7 | ENST00000635253.2 | c.2516A>G | p.His839Arg | missense_variant | 21/50 | 5 | NM_001367561.1 | ENSP00000489124 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152230Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251254Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135816
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GnomAD4 exome AF: 0.0000123 AC: 18AN: 1461632Hom.: 0 Cov.: 31 AF XY: 0.0000124 AC XY: 9AN XY: 727118
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GnomAD4 genome AF: 0.00000657 AC: 1AN: 152230Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74380
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 19, 2024 | Variant summary: DOCK7 c.2516A>G (p.His839Arg) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251254 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.2516A>G in individuals affected with Developmental And Epileptic Encephalopathy, 23 and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 566731). Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Developmental and epileptic encephalopathy, 23 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Aug 26, 2021 | This sequence change replaces histidine with arginine at codon 839 of the DOCK7 protein (p.His839Arg). The histidine residue is highly conserved and there is a small physicochemical difference between histidine and arginine. This variant is present in population databases (rs778470902, ExAC 0.001%). This variant has not been reported in the literature in individuals affected with DOCK7-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). 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. - |
Computational scores
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Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Uncertain
CADD
Benign
DANN
Uncertain
DEOGEN2
Uncertain
.;.;.;.;.;D;T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D;D;D;D;T
M_CAP
Benign
T
MetaRNN
Benign
T;T;T;T;T;T;T
MetaSVM
Benign
T
MutationAssessor
Benign
N;N;N;N;N;N;.
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
B;B;B;B;B;.;.
Vest4
MutPred
Gain of MoRF binding (P = 0.0532);Gain of MoRF binding (P = 0.0532);Gain of MoRF binding (P = 0.0532);Gain of MoRF binding (P = 0.0532);Gain of MoRF binding (P = 0.0532);Gain of MoRF binding (P = 0.0532);.;
MVP
MPC
0.53
ClinPred
T
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at