rs2056943

Positions:

• chr6-15524332-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000338950.9(DTNBP1):​c.*93A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0375 in 1,611,786 control chromosomes in the GnomAD database, including 1,222 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.029 (85 hom., cov: 33)
  • Exomes 𝑓: 0.038 (1137 hom.)
• Consequence: DTNBP1 ENST00000338950.9 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.551

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 6-15524332-T-C is Benign according to our data. Variant chr6-15524332-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 1214828.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 = 0.0293 (4462/152202) while in subpopulation NFE AF= 0.0456 (3101/68004). AF 95% confidence interval is 0.0443. There are 85 homozygotes in gnomad4. There are 2122 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 85 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DTNBP1	NM_032122.5	c.811+194A>G		intron_variant		ENST00000344537.10	NP_115498.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DTNBP1	ENST00000344537.10	c.811+194A>G		intron_variant		1	NM_032122.5	ENSP00000341680	P1

Frequencies

GnomAD3 genomes AF: 0.0294 AC: 4467 AN: 152084 Hom.: 85 Cov.: 33

Gnomad AFR AF: 0.00708

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.0296

Gnomad ASJ AF: 0.0300

Gnomad EAS AF: 0.000579

Gnomad SAS AF: 0.0137

Gnomad FIN AF: 0.0350

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0456

Gnomad OTH AF: 0.0306

GnomAD3 exomes AF: 0.0311 AC: 7824 AN: 251420 Hom.: 161 AF XY: 0.0311 AC XY: 4227 AN XY: 135882

Gnomad AFR exome AF: 0.00683

Gnomad AMR exome AF: 0.0198

Gnomad ASJ exome AF: 0.0342

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0157

Gnomad FIN exome AF: 0.0400

Gnomad NFE exome AF: 0.0451

Gnomad OTH exome AF: 0.0344

GnomAD4 exome AF: 0.0384 AC: 56041 AN: 1459584 Hom.: 1137 Cov.: 35 AF XY: 0.0380 AC XY: 27596 AN XY: 726122

Gnomad4 AFR exome AF: 0.00634

Gnomad4 AMR exome AF: 0.0207

Gnomad4 ASJ exome AF: 0.0341

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0152

Gnomad4 FIN exome AF: 0.0410

Gnomad4 NFE exome AF: 0.0434

Gnomad4 OTH exome AF: 0.0355

GnomAD4 genome AF: 0.0293 AC: 4462 AN: 152202 Hom.: 85 Cov.: 33 AF XY: 0.0285 AC XY: 2122 AN XY: 74426

Gnomad4 AFR AF: 0.00706

Gnomad4 AMR AF: 0.0295

Gnomad4 ASJ AF: 0.0300

Gnomad4 EAS AF: 0.000580

Gnomad4 SAS AF: 0.0135

Gnomad4 FIN AF: 0.0350

Gnomad4 NFE AF: 0.0456

Gnomad4 OTH AF: 0.0298

Alfa AF: 0.0401 Hom.: 222

Bravo AF: 0.0270

Asia WGS AF: 0.00577 AC: 20 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely 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	-0.90
CADD	Benign	0.86
DANN	Benign	0.74

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: rs2056943; hg19: chr6-15524563;