Genetic Variant DOK5:c.*617C>G (chr20-54651096-C-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_018431.5(DOK5):c.*617C>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.449 in 151,932 control chromosomes in the GnomAD database, including 17,046 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.45 ( 17046 hom., cov: 33)

Exomes 𝑓: 0.43 ( 3 hom. )

Failed GnomAD Quality Control

Consequence

DOK5
NM_018431.5 3_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -3.10

Publications

4 publications found

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 was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.87).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.541 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein
DOK5	NM_018431.5 link	c.*617C>G	3_prime_UTR_variant	Exon 8 of 8	ENST00000262593.10	NP_060901.2
DOK5	NM_177959.3 link	c.*617C>G	3_prime_UTR_variant	Exon 8 of 8		NP_808874.1
DOK5	XM_024451946.2 link	c.*617C>G	3_prime_UTR_variant	Exon 8 of 8		XP_024307714.1
DOK5	XM_011528904.2 link	c.*617C>G	3_prime_UTR_variant	Exon 8 of 8		XP_011527206.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DOK5	ENST00000262593.10 link	c.*617C>G		3_prime_UTR_variant	Exon 8 of 8	1	NM_018431.5	ENSP00000262593.5
DOK5	ENST00000395939.5 link	c.*617C>G		downstream_gene_variant		1		ENSP00000379270.1

Frequencies

GnomAD3 genomes

AF:

0.450

AC:

68248

AN:

151812

Hom.:

17034

Cov.:

show subpopulations

Gnomad AFR

AF:

0.225

Gnomad AMI

AF:

0.537

Gnomad AMR

AF:

0.486

Gnomad ASJ

AF:

0.715

Gnomad EAS

AF:

0.450

Gnomad SAS

AF:

0.529

Gnomad FIN

AF:

0.501

Gnomad MID

AF:

0.694

Gnomad NFE

AF:

0.546

Gnomad OTH

AF:

0.522

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.433

AC:

AN:

Hom.:

Cov.:

AF XY:

0.409

AC XY:

AN XY:

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.250

AC:

AN:

American (AMR)

AF:

1.00

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AF:

0.500

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.409

AC:

AN:

Other (OTH)

AC:

AN:

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00911032), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.396

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.449

AC:

68291

AN:

151932

Hom.:

17046

Cov.:

AF XY:

0.451

AC XY:

33517

AN XY:

74242

show subpopulations

African (AFR)

AF:

0.226

AC:

9359

AN:

41476

American (AMR)

AF:

0.486

AC:

7417

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.715

AC:

2479

AN:

3466

East Asian (EAS)

AF:

0.450

AC:

2321

AN:

5158

South Asian (SAS)

AF:

0.531

AC:

2554

AN:

4812

European-Finnish (FIN)

AF:

0.501

AC:

5283

AN:

10536

Middle Eastern (MID)

AF:

0.699

AC:

204

AN:

292

European-Non Finnish (NFE)

AF:

0.546

AC:

37079

AN:

67908

Other (OTH)

AF:

0.526

AC:

1106

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1836

3672

5508

7344

9180

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

632

1264

1896

2528

3160

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.483

Hom.:

2328

Bravo

AF:

0.438

Asia WGS

AF:

0.501

AC:

1745

AN:

3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

0.025

(source)

DANN

Benign

0.45

PhyloP100

-3.1

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over