rs16876571

Positions:

• chr6-15524448-G-A

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.889C>T​(p.His297Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0167 in 1,614,060 control chromosomes in the GnomAD database, including 251 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/14 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (24 hom., cov: 33)
  • Exomes 𝑓: 0.017 (227 hom.)
• Consequence: DTNBP1 ENST00000338950.9 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.259

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=0.003471464).
• BP6: Variant 6-15524448-G-A is Benign according to our data. Variant chr6-15524448-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 163301.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-15524448-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0126 (1926/152294) while in subpopulation NFE AF= 0.0203 (1381/68012). AF 95% confidence interval is 0.0194. There are 24 homozygotes in gnomad4. There are 883 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 24 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DTNBP1	NM_032122.5	c.811+78C>T		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+78C>T		intron_variant		1	NM_032122.5	ENSP00000341680	P1

Frequencies

GnomAD3 genomes AF: 0.0127 AC: 1927 AN: 152176 Hom.: 24 Cov.: 33

Gnomad AFR AF: 0.00369

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.0145

Gnomad ASJ AF: 0.00922

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00290

Gnomad FIN AF: 0.00800

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0203

Gnomad OTH AF: 0.0144

GnomAD3 exomes AF: 0.0115 AC: 2888 AN: 251448 Hom.: 30 AF XY: 0.0116 AC XY: 1577 AN XY: 135900

Gnomad AFR exome AF: 0.00381

Gnomad AMR exome AF: 0.00957

Gnomad ASJ exome AF: 0.0115

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00304

Gnomad FIN exome AF: 0.00956

Gnomad NFE exome AF: 0.0174

Gnomad OTH exome AF: 0.0155

GnomAD4 exome AF: 0.0171 AC: 24982 AN: 1461766 Hom.: 227 Cov.: 34 AF XY: 0.0167 AC XY: 12158 AN XY: 727160

Gnomad4 AFR exome AF: 0.00245

Gnomad4 AMR exome AF: 0.0104

Gnomad4 ASJ exome AF: 0.0106

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00260

Gnomad4 FIN exome AF: 0.0101

Gnomad4 NFE exome AF: 0.0202

Gnomad4 OTH exome AF: 0.0144

GnomAD4 genome AF: 0.0126 AC: 1926 AN: 152294 Hom.: 24 Cov.: 33 AF XY: 0.0119 AC XY: 883 AN XY: 74482

Gnomad4 AFR AF: 0.00370

Gnomad4 AMR AF: 0.0144

Gnomad4 ASJ AF: 0.00922

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00290

Gnomad4 FIN AF: 0.00800

Gnomad4 NFE AF: 0.0203

Gnomad4 OTH AF: 0.0142

Alfa AF: 0.0172 Hom.: 29

Bravo AF: 0.0135

TwinsUK AF: 0.0200 AC: 74

ALSPAC AF: 0.0171 AC: 66

ESP6500AA AF: 0.00409 AC: 18

ESP6500EA AF: 0.0230 AC: 198

ExAC AF: 0.0112 AC: 1361

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.0204

EpiControl AF: 0.0183

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 14, 2018	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Feb 21, 2013

His297Tyr in exon 9A of DTNBP1: This variant is not expected to have clinical si gnificance because it has been identified in 2.3% (198/8600) of European America n chromosomes from a broad population by the NHLBI Exome Sequencing Project (htt p://evs.gs.washington.edu/EVS; dbSNP rs16876571). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	1.9
DANN	Benign	0.86
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.0099	N
LIST_S2	Benign	0.28	T
MetaRNN	Benign	0.0035	T
MetaSVM	Benign	-0.96	T
MutationTaster	Benign	1.0	N;N;N;N;N
PROVEAN	Benign	-0.80	N
REVEL	Benign	0.052
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.042	D
Polyphen		0.038	B
Vest4		0.074
ClinPred		0.013	T
GERP RS		-4.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs16876571; hg19: chr6-15524679;