Variant 20-54610509-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_018431.5(DOK5):c.721G>A(p.Val241Met) variant causes a missense change. The variant allele was found at a frequency of 0.0000086 in 1,511,006 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000081 ( 0 hom. )

Consequence

DOK5
NM_018431.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.22

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.109883666).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DOK5	NM_018431.5 link	c.721G>A	p.Val241Met	missense_variant	Exon 6 of 8	ENST00000262593.10	NP_060901.2	Q9P104-1
DOK5	NM_177959.3 link	c.397G>A	p.Val133Met	missense_variant	Exon 6 of 8		NP_808874.1	Q9P104-2
DOK5	XM_024451946.2 link	c.685G>A	p.Val229Met	missense_variant	Exon 6 of 8		XP_024307714.1
DOK5	XM_011528904.2 link	c.397G>A	p.Val133Met	missense_variant	Exon 6 of 8		XP_011527206.1	Q9P104-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DOK5	ENST00000262593.10 link	c.721G>A	p.Val241Met	missense_variant	Exon 6 of 8	1	NM_018431.5	ENSP00000262593.5		Q9P104-1
DOK5	ENST00000395939.5 link	c.397G>A	p.Val133Met	missense_variant	Exon 6 of 8	1		ENSP00000379270.1		Q9P104-2

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152212

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000365

AC:

AN:

191714

Hom.:

AF XY:

0.0000477

AC XY:

AN XY:

104768

show subpopulations

Gnomad AFR exome

AF:

0.0000698

Gnomad AMR exome

AF:

0.000278

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:

0.0000105

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000810

AC:

AN:

1358794

Hom.:

Cov.:

AF XY:

0.0000105

AC XY:

AN XY:

669090

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000285

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:

9.44e-7

Gnomad4 OTH exome

AF:

0.0000362

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152212

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74356

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000642

ExAC

AF:

0.0000330

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 15, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.721G>A (p.V241M) alteration is located in exon 6 (coding exon 6) of the DOK5 gene. This alteration results from a G to A substitution at nucleotide position 721, causing the valine (V) at amino acid position 241 to be replaced by a methionine (M). 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

Benign

0.079

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.33

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.019

T;.

Eigen

Benign

-0.11

Eigen_PC

Benign

0.15

FATHMM_MKL

Uncertain

0.84

LIST_S2

Benign

0.83

T;T

M_CAP

Benign

0.018

MetaRNN

Benign

0.11

T;T

MetaSVM

Benign

-0.63

MutationAssessor

Benign

-0.040

N;.

PrimateAI

Uncertain

0.59

PROVEAN

Benign

0.78

N;N

REVEL

Uncertain

0.45

Sift

Benign

0.12

T;T

Sift4G

Benign

0.11

T;T

Polyphen

0.14

B;B

Vest4

0.22

MutPred

0.33

Loss of catalytic residue at V241 (P = 0.0061);.;

MVP

0.87

MPC

0.39

ClinPred

0.040

GERP RS

5.8

Varity_R

0.17

gMVP

0.32

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