20-54643555-C-T

Position:

chr20-54643555-C-T

Variant summary

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

The NM_018431.5(DOK5):c.833C>T(p.Thr278Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000267 in 1,460,756 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 0.0 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000027 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

DOK5
NM_018431.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.40

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=0.24445555).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
DOK5	NM_018431.5 linkuse as main transcript	c.833C>T	p.Thr278Met	missense_variant	7/8	ENST00000262593.10	NP_060901.2
DOK5	NM_177959.3 linkuse as main transcript	c.509C>T	p.Thr170Met	missense_variant	7/8		NP_808874.1
DOK5	XM_024451946.2 linkuse as main transcript	c.797C>T	p.Thr266Met	missense_variant	7/8		XP_024307714.1
DOK5	XM_011528904.2 linkuse as main transcript	c.509C>T	p.Thr170Met	missense_variant	7/8		XP_011527206.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DOK5	ENST00000262593.10 linkuse as main transcript	c.833C>T	p.Thr278Met	missense_variant	7/8	1	NM_018431.5	ENSP00000262593	P1	Q9P104-1
DOK5	ENST00000395939.5 linkuse as main transcript	c.509C>T	p.Thr170Met	missense_variant	7/8	1		ENSP00000379270		Q9P104-2

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

152240

Hom.:

Cov.:

FAILED QC

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000281

AC:

AN:

249318

Hom.:

AF XY:

0.0000371

AC XY:

AN XY:

134840

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:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000531

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000267

AC:

AN:

1460756

Hom.:

Cov.:

AF XY:

0.0000275

AC XY:

AN XY:

726692

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.0000382

Gnomad4 NFE exome

AF:

0.0000279

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

152240

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74376

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

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:

0.0000113

ExAC

AF:

0.0000494

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000296

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

Feb 17, 2024

The c.833C>T (p.T278M) alteration is located in exon 7 (coding exon 7) of the DOK5 gene. This alteration results from a C to T substitution at nucleotide position 833, causing the threonine (T) at amino acid position 278 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

0.077

BayesDel_addAF

Benign

-0.040

BayesDel_noAF

Benign

-0.14

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.021

T;.

Eigen

Benign

0.15

Eigen_PC

Uncertain

0.29

FATHMM_MKL

Benign

0.72

LIST_S2

Uncertain

0.89

D;D

M_CAP

Benign

0.043

MetaRNN

Benign

0.24

T;T

MetaSVM

Uncertain

0.27

MutationAssessor

Benign

1.1

L;.

MutationTaster

Benign

0.70

D;D

PrimateAI

Uncertain

0.60

PROVEAN

Benign

-0.88

N;N

REVEL

Uncertain

0.30

Sift

Uncertain

0.011

D;D

Sift4G

Uncertain

0.048

D;D

Polyphen

0.37

B;P

Vest4

0.45

MutPred

0.47

Gain of MoRF binding (P = 0.0728);.;

MVP

0.96

MPC

0.41

ClinPred

0.26

GERP RS

5.4

Varity_R

0.043

gMVP

0.60

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