6-15593088-GAAAAA-GAAAAAAA

Variant names:

• chr6-15593088-G-GAA
• rs199770715
• NM_032122.5:c.489-9_489-8dupTT

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2 BP6_Moderate BS1

The NM_032122.5(DTNBP1):​c.489-9_489-8dupTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00395 in 1,337,694 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.00085 (0 hom., cov: 28)
  • Exomes 𝑓: 0.0043 (0 hom.)
• Consequence: DTNBP1 NM_032122.5 splice_region, intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• 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: Likely_benign. The variant received -4 ACMG points.

• PM2: Variant has high frequency in the EAS (0.00987) population. However there is too low homozygotes in high coverage region: (expected more than 5, got 0).
• BP6: Variant 6-15593088-G-GAA is Benign according to our data. Variant chr6-15593088-G-GAA is described in ClinVar as Benign. ClinVar VariationId is 1336309.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000854 (116/135882) while in subpopulation AFR AF = 0.00243 (91/37500). AF 95% confidence interval is 0.00202. There are 0 homozygotes in GnomAd4. There are 64 alleles in the male GnomAd4 subpopulation. Median coverage is 28. This position passed quality control check.

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes AF: 0.000854 AC: 116 AN: 135848 Hom.: 0 Cov.: 28

Gnomad AFR AF: 0.00243

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000442

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000823

Gnomad SAS AF: 0.000232

Gnomad FIN AF: 0.000680

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000145

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0101 AC: 988 AN: 98290 AF XY: 0.0105

Gnomad AFR exome AF: 0.0161

Gnomad AMR exome AF: 0.0126

Gnomad ASJ exome AF: 0.00492

Gnomad EAS exome AF: 0.0230

Gnomad FIN exome AF: 0.00284

Gnomad NFE exome AF: 0.00726

Gnomad OTH exome AF: 0.00994

GnomAD4 exome AF: 0.00430 AC: 5166 AN: 1201812 Hom.: 0 Cov.: 0 AF XY: 0.00442 AC XY: 2649 AN XY: 598690

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

African (AFR) AF: 0.0101 AC: 267 AN: 26362

American (AMR) AF: 0.00749 AC: 215 AN: 28698

Ashkenazi Jewish (ASJ) AF: 0.00376 AC: 82 AN: 21828

East Asian (EAS) AF: 0.0108 AC: 378 AN: 35116

South Asian (SAS) AF: 0.00975 AC: 663 AN: 68024

European-Finnish (FIN) AF: 0.00216 AC: 99 AN: 45798

Middle Eastern (MID) AF: 0.00313 AC: 15 AN: 4798

European-Non Finnish (NFE) AF: 0.00349 AC: 3213 AN: 920982

Other (OTH) AF: 0.00466 AC: 234 AN: 50206

⚠️ 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: 0.000854 AC: 116 AN: 135882 Hom.: 0 Cov.: 28 AF XY: 0.000977 AC XY: 64 AN XY: 65514

African (AFR) AF: 0.00243 AC: 91 AN: 37500

American (AMR) AF: 0.000442 AC: 6 AN: 13586

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3238

East Asian (EAS) AF: 0.000827 AC: 4 AN: 4838

South Asian (SAS) AF: 0.000232 AC: 1 AN: 4304

European-Finnish (FIN) AF: 0.000680 AC: 5 AN: 7348

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 272

European-Non Finnish (NFE) AF: 0.000145 AC: 9 AN: 62074

Other (OTH) AF: 0.00 AC: 0 AN: 1876

Alfa AF: 0.00387 Hom.: 18

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Nov 07, 2017

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

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

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs199770715; hg19: chr6-15593319;