rs16876569

chr6-15524430-C-T

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.907G>A(p.Ala303Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00539 in 1,614,120 control chromosomes in the GnomAD database, including 28 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/15 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0041 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0055 (27 hom.)
• Consequence: DTNBP1 ENST00000338950.9 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.40

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 (MetaRNN=0.0029644072).
• BP6: Variant 6-15524430-C-T is Benign according to our data. Variant chr6-15524430-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 163300.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-15524430-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00408 (622/152274) while in subpopulation NFE AF= 0.00622 (423/68036). AF 95% confidence interval is 0.00573. There are 1 homozygotes in gnomad4. There are 320 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DTNBP1	NM_032122.5	c.811+96G>A		intron_variant		ENST00000344537.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DTNBP1	ENST00000344537.10	c.811+96G>A		intron_variant		1	NM_032122.5	P1

Frequencies

GnomAD3 genomes AF: 0.00409 AC: 622 AN: 152156 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00126

Gnomad AMI AF: 0.0242

Gnomad AMR AF: 0.00497

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00187

Gnomad FIN AF: 0.00320

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00622

Gnomad OTH AF: 0.00240

GnomAD3 exomes AF: 0.00340 AC: 854 AN: 251472 Hom.: 5 AF XY: 0.00352 AC XY: 479 AN XY: 135906

Gnomad AFR exome AF: 0.000615

Gnomad AMR exome AF: 0.00153

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00229

Gnomad FIN exome AF: 0.00296

Gnomad NFE exome AF: 0.00559

Gnomad OTH exome AF: 0.00326

GnomAD4 exome AF: 0.00553 AC: 8079 AN: 1461846 Hom.: 27 Cov.: 34 AF XY: 0.00538 AC XY: 3913 AN XY: 727210

Gnomad4 AFR exome AF: 0.000657

Gnomad4 AMR exome AF: 0.00172

Gnomad4 ASJ exome AF: 0.000115

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00240

Gnomad4 FIN exome AF: 0.00294

Gnomad4 NFE exome AF: 0.00654

Gnomad4 OTH exome AF: 0.00553

GnomAD4 genome AF: 0.00408 AC: 622 AN: 152274 Hom.: 1 Cov.: 33 AF XY: 0.00430 AC XY: 320 AN XY: 74436

Gnomad4 AFR AF: 0.00125

Gnomad4 AMR AF: 0.00497

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00187

Gnomad4 FIN AF: 0.00320

Gnomad4 NFE AF: 0.00622

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00483 Hom.: 5

Bravo AF: 0.00394

TwinsUK AF: 0.00485 AC: 18

ALSPAC AF: 0.00727 AC: 28

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.00570 AC: 49

ExAC AF: 0.00344 AC: 417

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.00529

EpiControl AF: 0.00510

ClinVar

Significance: Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2023	DTNBP1: BP4, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Feb 21, 2013

Ala303Thr in exon 9A of DTNBP1: This variant is not expected to have clinical si gnificance because it has been identified in 0.6% (49/8600) of European American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS; dbSNP rs16876569). -

DTNBP1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 02, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.63
Cadd	Benign	1.5
Dann	Benign	0.63
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.0060	N
LIST_S2	Benign	0.23	T
M_CAP	Benign	0.0021	T
MetaRNN	Benign	0.0030	T
MetaSVM	Benign	-0.97	T
MutationTaster	Benign	1.0	N;N;N;N;N
PROVEAN	Benign	0.46	N
REVEL	Benign	0.0080
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.0	B
Vest4		0.081
MVP		0.040
ClinPred		0.027	T
GERP RS		-2.6

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs16876569; hg19: chr6-15524661; COSMIC: COSV59039202; COSMIC: COSV59039202;