rs771121025

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_024940.8(DOCK5):​c.44C>A​(p.Ala15Glu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,412 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A15V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

DOCK5
NM_024940.8 missense, splice_region

Scores

7
9
3
Splicing: ADA: 0.08005
2

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.26
Variant links:
Genes affected
DOCK5 (HGNC:23476): (dedicator of cytokinesis 5) This gene encodes a member of the dedicator of cytokinesis protein family. Members of this family act as guanine nucleotide exchange factors for small Rho family G proteins. The protein encoded by this gene is thought to associate with adaptors CRK and CRKL, and function in regulation of intestinal epithelial cell spreading and migration on collagen IV. Similar proteins in mouse and zebrafish also function in myoblast fusion. [provided by RefSeq, Oct 2016]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.97

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
DOCK5NM_024940.8 linkc.44C>A p.Ala15Glu missense_variant, splice_region_variant Exon 2 of 52 ENST00000276440.12 NP_079216.4 Q9H7D0-1Q68DL4
DOCK5NM_001322810.2 linkc.44C>A p.Ala15Glu missense_variant, splice_region_variant Exon 2 of 4 NP_001309739.1 B9A015

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
DOCK5ENST00000276440.12 linkc.44C>A p.Ala15Glu missense_variant, splice_region_variant Exon 2 of 52 1 NM_024940.8 ENSP00000276440.7 Q9H7D0-1
DOCK5ENST00000481100.5 linkc.44C>A p.Ala15Glu missense_variant, splice_region_variant Exon 2 of 11 1 ENSP00000429737.1 Q9H7D0-2
DOCK5ENST00000410074.5 linkc.44C>A p.Ala15Glu missense_variant, splice_region_variant Exon 2 of 4 2 ENSP00000387036.1 B9A015

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1460412
Hom.:
0
Cov.:
30
AF XY:
0.00000138
AC XY:
1
AN XY:
726454
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000180
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.98
BayesDel_addAF
Pathogenic
0.31
D
BayesDel_noAF
Pathogenic
0.21
CADD
Benign
22
DANN
Uncertain
0.99
DEOGEN2
Benign
0.26
T;.;T
Eigen
Uncertain
0.62
Eigen_PC
Uncertain
0.54
FATHMM_MKL
Benign
0.47
N
LIST_S2
Uncertain
0.92
D;D;D
M_CAP
Pathogenic
0.90
D
MetaRNN
Pathogenic
0.97
D;D;D
MetaSVM
Uncertain
0.49
D
MutationAssessor
Pathogenic
4.3
.;H;H
PrimateAI
Uncertain
0.72
T
PROVEAN
Uncertain
-3.9
D;D;D
REVEL
Pathogenic
0.77
Sift
Uncertain
0.0020
D;D;D
Sift4G
Uncertain
0.012
D;D;D
Polyphen
0.95
.;.;P
Vest4
0.90
MutPred
0.76
Loss of MoRF binding (P = 0.0682);Loss of MoRF binding (P = 0.0682);Loss of MoRF binding (P = 0.0682);
MVP
0.96
MPC
0.28
ClinPred
1.0
D
GERP RS
4.4
Varity_R
0.69
gMVP
0.85

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.080
dbscSNV1_RF
Benign
0.40
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

No publications associated with this variant yet.

Other links and lift over

hg19: chr8-25101190; API