NM_032122.5:c.489-8dupT

Variant names:

• chr6-15593088-G-GA
• rs199770715
• NM_032122.5:c.489-8dupT

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6 BA1

The NM_032122.5(DTNBP1):​c.489-8dupT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.206 in 1,236,686 control chromosomes in the GnomAD database, including 2,611 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.18 (2285 hom., cov: 28)
  • Exomes 𝑓: 0.21 (326 hom.)
• Consequence: DTNBP1 NM_032122.5 splice_region, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 0.127
• Publications: 2 publications found

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 Gene-Disease associations (from GenCC):

• Hermansky-Pudlak syndrome 7

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, G2P

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP6: Variant 6-15593088-G-GA is Benign according to our data. Variant chr6-15593088-G-GA is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 355969.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.326 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DTNBP1	NM_032122.5	c.489-8dupT		splice_region_variant, intron_variant	Intron 6 of 9	ENST00000344537.10	NP_115498.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DTNBP1	ENST00000344537.10	c.489-8_489-7insT		splice_region_variant, intron_variant	Intron 6 of 9	1	NM_032122.5	ENSP00000341680.6

Frequencies

GnomAD3 genomes AF: 0.178 AC: 24111 AN: 135696 Hom.: 2288 Cov.: 28

Gnomad AFR AF: 0.250

Gnomad AMI AF: 0.0721

Gnomad AMR AF: 0.177

Gnomad ASJ AF: 0.140

Gnomad EAS AF: 0.340

Gnomad SAS AF: 0.248

Gnomad FIN AF: 0.0776

Gnomad MID AF: 0.154

Gnomad NFE AF: 0.132

Gnomad OTH AF: 0.184

GnomAD2 exomes AF: 0.227 AC: 22320 AN: 98290 AF XY: 0.226

Gnomad AFR exome AF: 0.274

Gnomad AMR exome AF: 0.224

Gnomad ASJ exome AF: 0.228

Gnomad EAS exome AF: 0.316

Gnomad FIN exome AF: 0.170

Gnomad NFE exome AF: 0.199

Gnomad OTH exome AF: 0.225

GnomAD4 exome AF: 0.210 AC: 230914 AN: 1100954 Hom.: 326 Cov.: 0 AF XY: 0.209 AC XY: 114865 AN XY: 548704

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.276 AC: 6862 AN: 24872

American (AMR) AF: 0.181 AC: 4973 AN: 27546

Ashkenazi Jewish (ASJ) AF: 0.187 AC: 3801 AN: 20356

East Asian (EAS) AF: 0.286 AC: 9526 AN: 33298

South Asian (SAS) AF: 0.250 AC: 16068 AN: 64290

European-Finnish (FIN) AF: 0.127 AC: 5365 AN: 42202

Middle Eastern (MID) AF: 0.240 AC: 1094 AN: 4564

European-Non Finnish (NFE) AF: 0.207 AC: 173180 AN: 837600

Other (OTH) AF: 0.217 AC: 10045 AN: 46226

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.178 AC: 24117 AN: 135732 Hom.: 2285 Cov.: 28 AF XY: 0.179 AC XY: 11698 AN XY: 65400

African (AFR) AF: 0.250 AC: 9367 AN: 37448

American (AMR) AF: 0.177 AC: 2399 AN: 13564

Ashkenazi Jewish (ASJ) AF: 0.140 AC: 453 AN: 3238

East Asian (EAS) AF: 0.340 AC: 1644 AN: 4834

South Asian (SAS) AF: 0.249 AC: 1068 AN: 4294

European-Finnish (FIN) AF: 0.0776 AC: 569 AN: 7332

Middle Eastern (MID) AF: 0.156 AC: 42 AN: 270

European-Non Finnish (NFE) AF: 0.132 AC: 8162 AN: 62032

Other (OTH) AF: 0.188 AC: 352 AN: 1874

Alfa AF: 0.0694 Hom.: 18

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:3

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:2

-

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Aug 20, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hermansky-Pudlak syndrome Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.13
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs199770715; hg19: chr6-15593319; COSMIC: COSV59036741;