dbSNP rs16876571: DTNBP1:p.His297Tyr (chr6-15524448-G-A) – ACMG Classification: Benign (-20 pts)

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. 13/17 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

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), G2P, ClinGen

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 Benign/Likely_benign. ClinVar VariationId is 163301.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 passed quality control check.

BS2

High Homozygotes in GnomAd4 at 24 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_183040.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DTNBP1	NM_032122.5	MANE Select	c.811+78C>T		intron	N/A	NP_115498.2
DTNBP1	NM_183040.2		c.889C>T	p.His297Tyr	missense	Exon 9 of 9	NP_898861.1	Q96EV8-2
DTNBP1	NM_001271668.2		c.760+78C>T		intron	N/A	NP_001258597.1	A6NFV8

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DTNBP1	ENST00000338950.9	TSL:1	c.889C>T	p.His297Tyr	missense	Exon 9 of 9	ENSP00000344718.5	Q96EV8-2
DTNBP1	ENST00000344537.10	TSL:1 MANE Select	c.811+78C>T		intron	N/A	ENSP00000341680.6	Q96EV8-1
DTNBP1	ENST00000622898.4	TSL:1	c.706+78C>T		intron	N/A	ENSP00000481997.1	A0A087WYP9

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

African (AFR)

AF:

0.00245

AC:

AN:

33478

American (AMR)

AF:

0.0104

AC:

467

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0106

AC:

277

AN:

26132

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39700

South Asian (SAS)

AF:

0.00260

AC:

224

AN:

86252

European-Finnish (FIN)

AF:

0.0101

AC:

539

AN:

53414

Middle Eastern (MID)

AF:

0.00503

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0202

AC:

22492

AN:

1111908

Other (OTH)

AF:

0.0144

AC:

870

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

1574

3148

4722

6296

7870

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

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

African (AFR)

AF:

0.00370

AC:

154

AN:

41584

American (AMR)

AF:

0.0144

AC:

220

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00922

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5182

South Asian (SAS)

AF:

0.00290

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00800

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0203

AC:

1381

AN:

68012

Other (OTH)

AF:

0.0142

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

103

206

309

412

515

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

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

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.077

BayesDel_addAF

Benign

-0.63

BayesDel_noAF

Benign

-0.67

CADD

Benign

1.9

(source)

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

PhyloP100

-0.26

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

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over