dbSNP rs15899: DOK5:c.*609T>C (chr20-54651088-T-C) – 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.*609T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.445 in 151,944 control chromosomes in the GnomAD database, including 16,696 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 0.44 ( 16696 hom., cov: 33)

Exomes 𝑓: 0.42 ( 4 hom. )

Failed GnomAD Quality Control

Consequence

DOK5
NM_018431.5 3_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.629

Publications

5 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=-0.9).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.537 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
DOK5	NM_018431.5 link	c.*609T>C	3_prime_UTR_variant	Exon 8 of 8	ENST00000262593.10	NP_060901.2	Q9P104-1
DOK5	NM_177959.3 link	c.*609T>C	3_prime_UTR_variant	Exon 8 of 8		NP_808874.1	Q9P104-2
DOK5	XM_024451946.2 link	c.*609T>C	3_prime_UTR_variant	Exon 8 of 8		XP_024307714.1
DOK5	XM_011528904.2 link	c.*609T>C	3_prime_UTR_variant	Exon 8 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.*609T>C		3_prime_UTR_variant	Exon 8 of 8	1	NM_018431.5	ENSP00000262593.5		Q9P104-1
DOK5	ENST00000395939.5 link	c.*609T>C		downstream_gene_variant		1		ENSP00000379270.1		Q9P104-2

Frequencies

GnomAD3 genomes

AF:

0.445

AC:

67534

AN:

151824

Hom.:

16685

Cov.:

show subpopulations

Gnomad AFR

AF:

0.219

Gnomad AMI

AF:

0.540

Gnomad AMR

AF:

0.478

Gnomad ASJ

AF:

0.712

Gnomad EAS

AF:

0.447

Gnomad SAS

AF:

0.526

Gnomad FIN

AF:

0.502

Gnomad MID

AF:

0.685

Gnomad NFE

AF:

0.542

Gnomad OTH

AF:

0.515

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.417

AC:

AN:

Hom.:

Cov.:

AF XY:

0.333

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)

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.400

AC:

AN:

Other (OTH)

AC:

AN:

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00367175), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.389

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

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:

0.445

AC:

67574

AN:

151944

Hom.:

16696

Cov.:

AF XY:

0.447

AC XY:

33178

AN XY:

74240

show subpopulations

African (AFR)

AF:

0.220

AC:

9113

AN:

41506

American (AMR)

AF:

0.478

AC:

7299

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.712

AC:

2468

AN:

3464

East Asian (EAS)

AF:

0.447

AC:

2307

AN:

5158

South Asian (SAS)

AF:

0.528

AC:

2537

AN:

4808

European-Finnish (FIN)

AF:

0.502

AC:

5289

AN:

10544

Middle Eastern (MID)

AF:

0.688

AC:

201

AN:

292

European-Non Finnish (NFE)

AF:

0.542

AC:

36780

AN:

67886

Other (OTH)

AF:

0.520

AC:

1091

AN:

2100

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1802

3604

5407

7209

9011

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

626

1252

1878

2504

3130

<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:

0.518

Hom.:

82640

Bravo

AF:

0.434

Asia WGS

AF:

0.498

AC:

1734

AN:

3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

0.93

(source)

DANN

Benign

0.47

PhyloP100

-0.63

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