rs16876573

Variant names:

• chr6-15524467-T-C
• rs16876573
• ENST00000338950.9:c.870A>G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_183040.2(DTNBP1):​c.870A>G​(p.Pro290Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0405 in 1,613,570 control chromosomes in the GnomAD database, including 1,618 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.032 (116 hom., cov: 32)
  • Exomes 𝑓: 0.041 (1502 hom.)
• Consequence: DTNBP1 NM_183040.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.161

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 6-15524467-T-C is Benign according to our data. Variant chr6-15524467-T-C is described in ClinVar as [Benign]. Clinvar id is 178772.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-15524467-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.161 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0632 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DTNBP1	NM_032122.5	c.811+59A>G		intron_variant	Intron 9 of 9	ENST00000344537.10	NP_115498.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DTNBP1	ENST00000344537.10	c.811+59A>G		intron_variant	Intron 9 of 9	1	NM_032122.5	ENSP00000341680.6

Frequencies

GnomAD3 genomes AF: 0.0320 AC: 4870 AN: 152142 Hom.: 112 Cov.: 32

Gnomad AFR AF: 0.0181

Gnomad AMI AF: 0.0175

Gnomad AMR AF: 0.0343

Gnomad ASJ AF: 0.0343

Gnomad EAS AF: 0.000580

Gnomad SAS AF: 0.0694

Gnomad FIN AF: 0.0121

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0426

Gnomad OTH AF: 0.0397

GnomAD3 exomes AF: 0.0356 AC: 8944 AN: 251342 Hom.: 232 AF XY: 0.0389 AC XY: 5281 AN XY: 135842

Gnomad AFR exome AF: 0.0178

Gnomad AMR exome AF: 0.0229

Gnomad ASJ exome AF: 0.0342

Gnomad EAS exome AF: 0.000217

Gnomad SAS exome AF: 0.0711

Gnomad FIN exome AF: 0.0132

Gnomad NFE exome AF: 0.0426

Gnomad OTH exome AF: 0.0342

GnomAD4 exome AF: 0.0413 AC: 60398 AN: 1461310 Hom.: 1502 Cov.: 34 AF XY: 0.0422 AC XY: 30670 AN XY: 726820

Gnomad4 AFR exome AF: 0.0176

Gnomad4 AMR exome AF: 0.0243

Gnomad4 ASJ exome AF: 0.0338

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.0712

Gnomad4 FIN exome AF: 0.0125

Gnomad4 NFE exome AF: 0.0436

Gnomad4 OTH exome AF: 0.0383

GnomAD4 genome AF: 0.0321 AC: 4885 AN: 152260 Hom.: 116 Cov.: 32 AF XY: 0.0323 AC XY: 2407 AN XY: 74442

Gnomad4 AFR AF: 0.0185

Gnomad4 AMR AF: 0.0341

Gnomad4 ASJ AF: 0.0343

Gnomad4 EAS AF: 0.000581

Gnomad4 SAS AF: 0.0693

Gnomad4 FIN AF: 0.0121

Gnomad4 NFE AF: 0.0426

Gnomad4 OTH AF: 0.0393

Alfa AF: 0.0387 Hom.: 66

Bravo AF: 0.0319

Asia WGS AF: 0.0270 AC: 92 AN: 3478

EpiCase AF: 0.0458

EpiControl AF: 0.0481

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Pro290Pro in exon 9A of DTNBP1: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue and is not located wi thin the splice consensus sequence. It has been identified in 4.3% (373/8600) of European American chromosomes from a broad population by the NHLBI Exome Sequen cing Project (http://evs.gs.washington.edu/EVS; dbSNP rs16876573). -

not provided Benign:1

Jul 14, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	1.7
DANN	Benign	0.42

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

LitVar

Other links and lift over

dbSNP: rs16876573; hg19: chr6-15524698;