chr6-15593088-GA-G

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_032122.5(DTNBP1):​c.489-8delT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.0022 (0 hom., cov: 28)
  • Exomes 𝑓: 0.13 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: DTNBP1 NM_032122.5 splice_region, intron
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2 B:2
• 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: Uncertain_significance. The variant received 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DTNBP1	NM_032122.5	c.489-8delT		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.489-8delT		splice_region_variant, intron_variant	Intron 6 of 9	1	NM_032122.5	ENSP00000341680.6

Frequencies

GnomAD3 genomes AF: 0.00217 AC: 295 AN: 135690 Hom.: 0 Cov.: 28

Gnomad AFR AF: 0.00249

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00354

Gnomad ASJ AF: 0.00865

Gnomad EAS AF: 0.000823

Gnomad SAS AF: 0.000463

Gnomad FIN AF: 0.00410

Gnomad MID AF: 0.00340

Gnomad NFE AF: 0.00136

Gnomad OTH AF: 0.00269

GnomAD2 exomes AF: 0.228 AC: 22454 AN: 98290 AF XY: 0.230

Gnomad AFR exome AF: 0.184

Gnomad AMR exome AF: 0.230

Gnomad ASJ exome AF: 0.247

Gnomad EAS exome AF: 0.148

Gnomad FIN exome AF: 0.281

Gnomad NFE exome AF: 0.248

Gnomad OTH exome AF: 0.235

GnomAD4 exome AF: 0.134 AC: 135198 AN: 1010718 Hom.: 0 Cov.: 0 AF XY: 0.135 AC XY: 67908 AN XY: 502030

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

African (AFR) AF: 0.105 AC: 2461 AN: 23440

American (AMR) AF: 0.167 AC: 4264 AN: 25530

Ashkenazi Jewish (ASJ) AF: 0.173 AC: 3117 AN: 17998

East Asian (EAS) AF: 0.107 AC: 3267 AN: 30458

South Asian (SAS) AF: 0.130 AC: 7811 AN: 60192

European-Finnish (FIN) AF: 0.200 AC: 6980 AN: 34976

Middle Eastern (MID) AF: 0.116 AC: 485 AN: 4178

European-Non Finnish (NFE) AF: 0.131 AC: 101071 AN: 771656

Other (OTH) AF: 0.136 AC: 5742 AN: 42290

⚠️ 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 Data not reliable, filtered out with message: AS_VQSR AF: 0.00219 AC: 297 AN: 135722 Hom.: 0 Cov.: 28 AF XY: 0.00211 AC XY: 138 AN XY: 65422

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

African (AFR) AF: 0.00248 AC: 93 AN: 37494

American (AMR) AF: 0.00354 AC: 48 AN: 13572

Ashkenazi Jewish (ASJ) AF: 0.00865 AC: 28 AN: 3236

East Asian (EAS) AF: 0.00103 AC: 5 AN: 4838

South Asian (SAS) AF: 0.000465 AC: 2 AN: 4302

European-Finnish (FIN) AF: 0.00410 AC: 30 AN: 7316

Middle Eastern (MID) AF: 0.00735 AC: 2 AN: 272

European-Non Finnish (NFE) AF: 0.00136 AC: 84 AN: 61972

Other (OTH) AF: 0.00267 AC: 5 AN: 1874

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0661 Hom.: 18

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2 Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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

Significance: Benign

Review Status: no assertion criteria provided

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

- -

not provided Uncertain:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.13
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs199770715; hg19: chr6-15593319; COSMIC: COSV59039896;