rs78181071

chr6-15524635-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Moderate BP6 BP7 BS1 BS2

The NM_032122.5(DTNBP1):c.702C>T(p.Asn234=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00348 in 1,613,746 control chromosomes in the GnomAD database, including 24 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0033 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0035 (23 hom.)
• Consequence: DTNBP1 NM_032122.5 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: -0.0250

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 6-15524635-G-A is Benign according to our data. Variant chr6-15524635-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 210858.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=1, Likely_benign=1}. Variant chr6-15524635-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.025 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00326 (496/152272) while in subpopulation SAS AF= 0.00539 (26/4824). AF 95% confidence interval is 0.00378. There are 1 homozygotes in gnomad4. There are 227 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DTNBP1	NM_032122.5	c.702C>T	p.Asn234=	synonymous_variant	9/10	ENST00000344537.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DTNBP1	ENST00000344537.10	c.702C>T	p.Asn234=	synonymous_variant	9/10	1	NM_032122.5	P1

Frequencies

GnomAD3 genomes AF: 0.00327 AC: 497 AN: 152154 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00302

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00393

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00539

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00393

Gnomad OTH AF: 0.00622

GnomAD3 exomes AF: 0.00309 AC: 772 AN: 249726 Hom.: 4 AF XY: 0.00347 AC XY: 469 AN XY: 135152

Gnomad AFR exome AF: 0.00388

Gnomad AMR exome AF: 0.00278

Gnomad ASJ exome AF: 0.000894

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00519

Gnomad FIN exome AF: 0.000188

Gnomad NFE exome AF: 0.00372

Gnomad OTH exome AF: 0.00376

GnomAD4 exome AF: 0.00350 AC: 5113 AN: 1461474 Hom.: 23 Cov.: 34 AF XY: 0.00356 AC XY: 2591 AN XY: 727036

Gnomad4 AFR exome AF: 0.00382

Gnomad4 AMR exome AF: 0.00295

Gnomad4 ASJ exome AF: 0.000842

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00550

Gnomad4 FIN exome AF: 0.000302

Gnomad4 NFE exome AF: 0.00364

Gnomad4 OTH exome AF: 0.00409

GnomAD4 genome AF: 0.00326 AC: 496 AN: 152272 Hom.: 1 Cov.: 33 AF XY: 0.00305 AC XY: 227 AN XY: 74438

Gnomad4 AFR AF: 0.00301

Gnomad4 AMR AF: 0.00392

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00539

Gnomad4 FIN AF: 0.0000943

Gnomad4 NFE AF: 0.00391

Gnomad4 OTH AF: 0.00616

Alfa AF: 0.00356 Hom.: 1

Bravo AF: 0.00351

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.00425

EpiControl AF: 0.00516

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2022	- -

not specified Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 11, 2015	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
Cadd	Benign	7.0
Dann	Benign	0.85

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: rs78181071; hg19: chr6-15524866; COSMIC: COSV59041994; COSMIC: COSV59041994;