13-98810219-C-T
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Variant summary
Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP2BP4_StrongBS1_SupportingBS2
The NM_001366683.2(DOCK9):c.5203G>A(p.Asp1735Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000698 in 1,613,888 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.00077 ( 1 hom., cov: 32)
Exomes 𝑓: 0.00069 ( 3 hom. )
Consequence
DOCK9
NM_001366683.2 missense
NM_001366683.2 missense
Scores
1
8
8
Clinical Significance
Conservation
PhyloP100: 4.60
Genes affected
DOCK9 (HGNC:14132): (dedicator of cytokinesis 9) Enables cadherin binding activity. Predicted to be involved in positive regulation of GTPase activity. Located in membrane. [provided by Alliance of Genome Resources, Apr 2022]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -8 ACMG points.
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), DOCK9. . Gene score misZ 3.0983 (greater than the threshold 3.09). Trascript score misZ 3.4483 (greater than threshold 3.09). GenCC has associacion of gene with keratoconus.
BP4
Computational evidence support a benign effect (MetaRNN=0.012893587).
BS1
Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000691 (1010/1461610) while in subpopulation MID AF= 0.0196 (113/5768). AF 95% confidence interval is 0.0167. There are 3 homozygotes in gnomad4_exome. There are 533 alleles in male gnomad4_exome subpopulation. Median coverage is 30. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
BS2
High Homozygotes in GnomAdExome4 at 3 gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
DOCK9 | NM_001366683.2 | c.5203G>A | p.Asp1735Asn | missense_variant | 46/53 | ENST00000682017.1 | NP_001353612.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
DOCK9 | ENST00000682017.1 | c.5203G>A | p.Asp1735Asn | missense_variant | 46/53 | NM_001366683.2 | ENSP00000507034.1 |
Frequencies
GnomAD3 genomes AF: 0.000775 AC: 118AN: 152160Hom.: 1 Cov.: 32
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GnomAD3 exomes AF: 0.000951 AC: 237AN: 249090Hom.: 2 AF XY: 0.00102 AC XY: 138AN XY: 135150
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GnomAD4 exome AF: 0.000691 AC: 1010AN: 1461610Hom.: 3 Cov.: 30 AF XY: 0.000733 AC XY: 533AN XY: 727090
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GnomAD4 genome AF: 0.000768 AC: 117AN: 152278Hom.: 1 Cov.: 32 AF XY: 0.000792 AC XY: 59AN XY: 74454
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 28, 2022 | The c.5206G>A (p.D1736N) alteration is located in exon 47 (coding exon 47) of the DOCK9 gene. This alteration results from a G to A substitution at nucleotide position 5206, causing the aspartic acid (D) at amino acid position 1736 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Pathogenic
DANN
Uncertain
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D;D;D
M_CAP
Benign
T
MetaRNN
Benign
T;T;T;T;T
MetaSVM
Benign
T
PrimateAI
Pathogenic
D
PROVEAN
Uncertain
.;N;.;D;D
REVEL
Benign
Sift
Uncertain
.;D;.;D;D
Sift4G
Uncertain
.;D;D;T;.
Polyphen
0.92, 0.90
.;P;.;.;P
Vest4
0.69, 0.61
MVP
MPC
0.73
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
gMVP
Splicing
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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