Variant 20-54591763-G-A details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_018431.5(DOK5):c.557G>A(p.Arg186Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000821 in 1,461,762 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000082 ( 0 hom. )

Consequence

DOK5
NM_018431.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.96

Variant links:

Genes affected

DOK5 (HGNC:16173): (docking protein 5) The protein encoded by this gene is a member of the DOK family of membrane proteins, which are adapter proteins involved in signal transduction. The encoded protein interacts with phosphorylated receptor tyrosine kinases to mediate neurite outgrowth and activation of the MAP kinase pathway. Unlike other DOK family proteins, this protein does not interact with RASGAP. This protein is up-regulated in patients with systemic sclerosis and is associated with fibrosis induced by insulin-like growth factor binding protein 5. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, Jun 2014]

DOK5 links:

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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, 0.962

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
DOK5	NM_018431.5 linkuse as main transcript	c.557G>A	p.Arg186Gln	missense_variant	5/8	ENST00000262593.10	NP_060901.2
DOK5	NM_177959.3 linkuse as main transcript	c.233G>A	p.Arg78Gln	missense_variant	5/8		NP_808874.1
DOK5	XM_024451946.2 linkuse as main transcript	c.521G>A	p.Arg174Gln	missense_variant	5/8		XP_024307714.1
DOK5	XM_011528904.2 linkuse as main transcript	c.233G>A	p.Arg78Gln	missense_variant	5/8		XP_011527206.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DOK5	ENST00000262593.10 linkuse as main transcript	c.557G>A	p.Arg186Gln	missense_variant	5/8	1	NM_018431.5	ENSP00000262593	P1	Q9P104-1
DOK5	ENST00000395939.5 linkuse as main transcript	c.233G>A	p.Arg78Gln	missense_variant	5/8	1		ENSP00000379270		Q9P104-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000797

AC:

AN:

251010

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135670

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000821

AC:

AN:

1461762

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

727182

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000899

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

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

Dec 27, 2023

The c.557G>A (p.R186Q) alteration is located in exon 5 (coding exon 5) of the DOK5 gene. This alteration results from a G to A substitution at nucleotide position 557, causing the arginine (R) at amino acid position 186 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.42

BayesDel_noAF

Pathogenic

0.38

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.88

D;.

Eigen

Pathogenic

0.92

Eigen_PC

Pathogenic

0.91

FATHMM_MKL

Uncertain

0.97

LIST_S2

Pathogenic

1.0

D;D

M_CAP

Uncertain

0.20

MetaRNN

Pathogenic

0.96

D;D

MetaSVM

Uncertain

0.59

MutationAssessor

Pathogenic

3.2

M;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.68

PROVEAN

Uncertain

-3.4

D;D

REVEL

Pathogenic

0.89

Sift

Uncertain

0.0020

D;D

Sift4G

Uncertain

0.0090

D;D

Polyphen

1.0

D;D

Vest4

0.98

MutPred

0.87

Loss of MoRF binding (P = 0.0283);.;

MVP

0.95

MPC

1.3

ClinPred

0.99

GERP RS

5.7

Varity_R

0.85

gMVP

0.66

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over