NM_032122.5:c.886C>T

Variant names:

Variant summary

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

The NM_032122.5(DTNBP1):c.886C>T(p.Pro296Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00239 in 1,614,228 control chromosomes in the GnomAD database, including 79 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P296R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.012 ( 37 hom., cov: 33)

Exomes 𝑓: 0.0014 ( 42 hom. )

Consequence

DTNBP1
NM_032122.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 2.82

Publications

7 publications found

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 Gene-Disease associations (from GenCC):

Hermansky-Pudlak syndrome 7
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, G2P

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=0.003545642).

BP6

Variant 6-15523145-G-A is Benign according to our data. Variant chr6-15523145-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 262013.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0123 (1867/152336) while in subpopulation AFR AF = 0.0415 (1725/41572). AF 95% confidence interval is 0.0399. There are 37 homozygotes in GnomAd4. There are 886 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 37 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DTNBP1	NM_032122.5 link	c.886C>T	p.Pro296Ser	missense_variant	Exon 10 of 10	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.886C>T	p.Pro296Ser	missense_variant	Exon 10 of 10	1	NM_032122.5	ENSP00000341680.6		Q96EV8-1

Frequencies

GnomAD3 genomes

AF:

0.0123

AC:

1867

AN:

152218

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0416

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00759

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.0100

GnomAD2 exomes

AF:

0.00316

AC:

794

AN:

251492

AF XY:

0.00235

show subpopulations

Gnomad AFR exome

AF:

0.0423

Gnomad AMR exome

AF:

0.00225

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000439

Gnomad OTH exome

AF:

0.00195

GnomAD4 exome

AF:

0.00136

AC:

1990

AN:

1461892

Hom.:

Cov.:

AF XY:

0.00124

AC XY:

900

AN XY:

727246

show subpopulations

African (AFR)

AF:

0.0464

AC:

1553

AN:

33480

American (AMR)

AF:

0.00284

AC:

127

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000568

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00433

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000378

AC:

AN:

1112012

Other (OTH)

AF:

0.00321

AC:

194

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

136

272

408

544

680

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

108

162

216

270

<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:

0.0123

AC:

1867

AN:

152336

Hom.:

Cov.:

AF XY:

0.0119

AC XY:

886

AN XY:

74504

show subpopulations

African (AFR)

AF:

0.0415

AC:

1725

AN:

41572

American (AMR)

AF:

0.00758

AC:

116

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.000207

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68024

Other (OTH)

AF:

0.00992

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

178

266

355

444

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00461

Hom.:

Bravo

AF:

0.0150

ESP6500AA

AF:

0.0422

AC:

186

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00372

AC:

452

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 28, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:2

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 09, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.066

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.56

CADD

Benign

7.9

(source)

DANN

Benign

0.60

DEOGEN2

Benign

0.059

T;.;T;.;.

Eigen

Benign

-0.70

Eigen_PC

Benign

-0.53

FATHMM_MKL

Benign

0.55

LIST_S2

Uncertain

0.91

D;D;D;D;D

MetaRNN

Benign

0.0035

T;T;T;T;T

MetaSVM

Benign

-0.92

MutationAssessor

Benign

1.0

L;.;.;.;.

PhyloP100

2.8

PrimateAI

Benign

0.25

PROVEAN

Benign

0.39

N;N;.;.;N

REVEL

Benign

0.086

Sift

Benign

0.91

T;T;.;.;T

Sift4G

Benign

1.0

T;T;T;T;.

Polyphen

0.0090

B;.;.;.;.

Vest4

0.065

MVP

0.29

MPC

0.15

ClinPred

0.0083

GERP RS

4.5

Varity_R

0.022

gMVP

0.069

Mutation Taster

=96/4

polymorphism

(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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over