chr6-15524448-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_183040.2(DTNBP1):c.889C>T(p.His297Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0167 in 1,614,060 control chromosomes in the GnomAD database, including 251 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.013 ( 24 hom., cov: 33)

Exomes 𝑓: 0.017 ( 227 hom. )

Consequence

DTNBP1
NM_183040.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.259

Variant links:

Genes affected

DTNBP1 (HGNC:17328): (dystrobrevin binding protein 1) This gene encodes a protein that may play a role in organelle biogenesis associated with melanosomes, platelet dense granules, and lysosomes. A similar protein in mouse is a component of a protein complex termed biogenesis of lysosome-related organelles complex 1 (BLOC-1), and binds to alpha- and beta-dystrobrevins, which are components of the dystrophin-associated protein complex (DPC). Mutations in this gene are associated with Hermansky-Pudlak syndrome type 7. This gene may also be associated with schizophrenia. Multiple transcript variants encoding distinct isoforms have been identified for this gene. [provided by RefSeq, Jul 2008]

DTNBP1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.003471464).

BP6

Variant 6-15524448-G-A is Benign according to our data. Variant chr6-15524448-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 163301.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-15524448-G-A is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0126 (1926/152294) while in subpopulation NFE AF = 0.0203 (1381/68012). AF 95% confidence interval is 0.0194. There are 24 homozygotes in GnomAd4. There are 883 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position FAILED quality control check.

BS2

High Homozygotes in GnomAd4 at 24 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DTNBP1	NM_032122.5 link	c.811+78C>T		intron_variant	Intron 9 of 9	ENST00000344537.10	NP_115498.2	Q96EV8-1A0A0S2Z5U8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DTNBP1	ENST00000344537.10 link	c.811+78C>T		intron_variant	Intron 9 of 9	1	NM_032122.5	ENSP00000341680.6		Q96EV8-1

Frequencies

GnomAD3 genomes

AF:

0.0127

AC:

1927

AN:

152176

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00369

Gnomad AMI

AF:

0.00548

Gnomad AMR

AF:

0.0145

Gnomad ASJ

AF:

0.00922

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00290

Gnomad FIN

AF:

0.00800

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.0203

Gnomad OTH

AF:

0.0144

GnomAD2 exomes

AF:

0.0115

AC:

2888

AN:

251448

AF XY:

0.0116

show subpopulations

Gnomad AFR exome

AF:

0.00381

Gnomad AMR exome

AF:

0.00957

Gnomad ASJ exome

AF:

0.0115

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00956

Gnomad NFE exome

AF:

0.0174

Gnomad OTH exome

AF:

0.0155

GnomAD4 exome

AF:

0.0171

AC:

24982

AN:

1461766

Hom.:

227

Cov.:

AF XY:

0.0167

AC XY:

12158

AN XY:

727160

show subpopulations

Gnomad4 AFR exome

AF:

0.00245

AC:

AN:

33478

Gnomad4 AMR exome

AF:

0.0104

AC:

467

AN:

44724

Gnomad4 ASJ exome

AF:

0.0106

AC:

277

AN:

26132

Gnomad4 EAS exome

AF:

0.0000504

AC:

AN:

39700

Gnomad4 SAS exome

AF:

0.00260

AC:

224

AN:

86252

Gnomad4 FIN exome

AF:

0.0101

AC:

539

AN:

53414

Gnomad4 NFE exome

AF:

0.0202

AC:

22492

AN:

1111908

Gnomad4 Remaining exome

AF:

0.0144

AC:

870

AN:

60390

Heterozygous variant carriers

1574

3148

4722

6296

7870

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Exome Hom

Variant carriers

836

1672

2508

3344

4180

<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:

0.0126

AC:

1926

AN:

152294

Hom.:

Cov.:

AF XY:

0.0119

AC XY:

883

AN XY:

74482

show subpopulations

Gnomad4 AFR

AF:

0.00370

AC:

0.00370335

AN:

0.00370335

Gnomad4 AMR

AF:

0.0144

AC:

0.0143941

AN:

0.0143941

Gnomad4 ASJ

AF:

0.00922

AC:

0.00921659

AN:

0.00921659

Gnomad4 EAS

AF:

0.000193

AC:

0.000192976

AN:

0.000192976

Gnomad4 SAS

AF:

0.00290

AC:

0.00290336

AN:

0.00290336

Gnomad4 FIN

AF:

0.00800

AC:

0.00800226

AN:

0.00800226

Gnomad4 NFE

AF:

0.0203

AC:

0.0203052

AN:

0.0203052

Gnomad4 OTH

AF:

0.0142

AC:

0.014218

AN:

0.014218

Heterozygous variant carriers

103

206

309

412

515

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

Genome Hom

Variant carriers

120

<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:

0.0175

Hom.:

Bravo

AF:

0.0135

TwinsUK

AF:

0.0200

AC:

ALSPAC

AF:

0.0171

AC:

ESP6500AA

AF:

0.00409

AC:

ESP6500EA

AF:

0.0230

AC:

198

ExAC

AF:

0.0112

AC:

1361

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.0204

EpiControl

AF:

0.0183

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jul 14, 2018

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Feb 21, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

His297Tyr in exon 9A of DTNBP1: This variant is not expected to have clinical si gnificance because it has been identified in 2.3% (198/8600) of European America n chromosomes from a broad population by the NHLBI Exome Sequencing Project (htt p://evs.gs.washington.edu/EVS; dbSNP rs16876571). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.63

BayesDel_noAF

Benign

-0.67

CADD

Benign

1.9

DANN

Benign

0.86

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.0099

LIST_S2

Benign

0.28

MetaRNN

Benign

0.0035

MetaSVM

Benign

-0.96

PROVEAN

Benign

-0.80

REVEL

Benign

0.052

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.042

Polyphen

0.038

Vest4

0.074

ClinPred

0.013

GERP RS

-4.7

Mutation Taster

=100/0

polymorphism

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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