rs3829893

Positions:

• chr6-15615406-G-A
• chr6-15615406-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_032122.5(DTNBP1):​c.356-7C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.157 in 1,613,078 control chromosomes in the GnomAD database, including 21,374 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (1860 hom., cov: 32)
  • Exomes 𝑓: 0.16 (19514 hom.)
• Consequence: DTNBP1 NM_032122.5 splice_region, intron
• Scores: Splicing: ADA: 0.00007164
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.951

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 6-15615406-G-A is Benign according to our data. Variant chr6-15615406-G-A is described in ClinVar as [Benign]. Clinvar id is 163302.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.289 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DTNBP1	NM_032122.5	c.356-7C>T		splice_region_variant, intron_variant		ENST00000344537.10	NP_115498.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DTNBP1	ENST00000344537.10	c.356-7C>T		splice_region_variant, intron_variant		1	NM_032122.5	ENSP00000341680.6

Frequencies

GnomAD3 genomes AF: 0.147 AC: 22341 AN: 152010 Hom.: 1860 Cov.: 32

Gnomad AFR AF: 0.0842

Gnomad AMI AF: 0.0969

Gnomad AMR AF: 0.171

Gnomad ASJ AF: 0.273

Gnomad EAS AF: 0.302

Gnomad SAS AF: 0.182

Gnomad FIN AF: 0.149

Gnomad MID AF: 0.250

Gnomad NFE AF: 0.158

Gnomad OTH AF: 0.188

GnomAD3 exomes AF: 0.170 AC: 42558 AN: 250606 Hom.: 4063 AF XY: 0.172 AC XY: 23312 AN XY: 135530

Gnomad AFR exome AF: 0.0842

Gnomad AMR exome AF: 0.165

Gnomad ASJ exome AF: 0.277

Gnomad EAS exome AF: 0.301

Gnomad SAS exome AF: 0.169

Gnomad FIN exome AF: 0.148

Gnomad NFE exome AF: 0.156

Gnomad OTH exome AF: 0.180

GnomAD4 exome AF: 0.159 AC: 231585 AN: 1460950 Hom.: 19514 Cov.: 32 AF XY: 0.161 AC XY: 116734 AN XY: 726814

Gnomad4 AFR exome AF: 0.0845

Gnomad4 AMR exome AF: 0.166

Gnomad4 ASJ exome AF: 0.274

Gnomad4 EAS exome AF: 0.272

Gnomad4 SAS exome AF: 0.172

Gnomad4 FIN exome AF: 0.143

Gnomad4 NFE exome AF: 0.152

Gnomad4 OTH exome AF: 0.175

GnomAD4 genome AF: 0.147 AC: 22353 AN: 152128 Hom.: 1860 Cov.: 32 AF XY: 0.150 AC XY: 11152 AN XY: 74368

Gnomad4 AFR AF: 0.0842

Gnomad4 AMR AF: 0.171

Gnomad4 ASJ AF: 0.273

Gnomad4 EAS AF: 0.302

Gnomad4 SAS AF: 0.182

Gnomad4 FIN AF: 0.149

Gnomad4 NFE AF: 0.158

Gnomad4 OTH AF: 0.188

Alfa AF: 0.165 Hom.: 5057

Bravo AF: 0.144

Asia WGS AF: 0.224 AC: 781 AN: 3476

EpiCase AF: 0.173

EpiControl AF: 0.175

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 21, 2013	356-7C>T in intron 5 of DTNBP1: This variant is not expected to have clinical si gnificance because it has been identified in 16.0% (1380/8600) of European Ameri can chromosomes from a broad population by the NHLBI Exome Sequencing Project (h ttp://evs.gs.washington.edu/EVS; dbSNP rs3829893). -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 09, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	4.1
DANN	Benign	0.47

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000072
dbscSNV1_RF	Benign	0.0060
SpliceAI score (max)		0.010		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: rs3829893; hg19: chr6-15615637; COSMIC: COSV59037366;