6-15593088-GAAAAA-GAAA

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_032122.5(DTNBP1):​c.489-9_489-8delTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00484 in 1,300,018 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000074 (0 hom., cov: 28)
  • Exomes 𝑓: 0.0054 (0 hom.)
• Consequence: DTNBP1 NM_032122.5 splice_region, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.140
• 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 2 ACMG points.

• PM2: Variant has high frequency in the AMR (0.0161) population. However there is too low homozygotes in high coverage region: (expected more than 7, got 0).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032122.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DTNBP1	NM_032122.5	MANE Select	c.489-9_489-8delTT		splice_region intron	N/A	NP_115498.2
	DTNBP1	NM_001271668.2		c.438-9_438-8delTT		splice_region intron	N/A	NP_001258597.1
	DTNBP1	NM_001271669.2		c.384-9_384-8delTT		splice_region intron	N/A	NP_001258598.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DTNBP1	ENST00000344537.10	TSL:1 MANE Select	c.489-9_489-8delTT		splice_region intron	N/A	ENSP00000341680.6
	DTNBP1	ENST00000622898.4	TSL:1	c.384-9_384-8delTT		splice_region intron	N/A	ENSP00000481997.1
	DTNBP1	ENST00000338950.9	TSL:1	c.489-9_489-8delTT		splice_region intron	N/A	ENSP00000344718.5

Frequencies

GnomAD3 genomes AF: 0.0000736 AC: 10 AN: 135800 Hom.: 0 Cov.: 28

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000147

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000409

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000806

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0259 AC: 2545 AN: 98290 AF XY: 0.0266

Gnomad AFR exome AF: 0.0303

Gnomad AMR exome AF: 0.0298

Gnomad ASJ exome AF: 0.0160

Gnomad EAS exome AF: 0.0290

Gnomad FIN exome AF: 0.0213

Gnomad NFE exome AF: 0.0282

Gnomad OTH exome AF: 0.0228

GnomAD4 exome AF: 0.00540 AC: 6284 AN: 1164186 Hom.: 0 AF XY: 0.00563 AC XY: 3266 AN XY: 580110

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

African (AFR) AF: 0.00630 AC: 162 AN: 25732

American (AMR) AF: 0.0174 AC: 479 AN: 27520

Ashkenazi Jewish (ASJ) AF: 0.00643 AC: 135 AN: 20992

East Asian (EAS) AF: 0.00832 AC: 284 AN: 34120

South Asian (SAS) AF: 0.00815 AC: 541 AN: 66340

European-Finnish (FIN) AF: 0.00888 AC: 387 AN: 43566

Middle Eastern (MID) AF: 0.00620 AC: 29 AN: 4680

European-Non Finnish (NFE) AF: 0.00443 AC: 3956 AN: 892640

Other (OTH) AF: 0.00640 AC: 311 AN: 48596

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000736 AC: 10 AN: 135832 Hom.: 0 Cov.: 28 AF XY: 0.0000916 AC XY: 6 AN XY: 65486

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

African (AFR) AF: 0.00 AC: 0 AN: 37502

American (AMR) AF: 0.000147 AC: 2 AN: 13580

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 4836

South Asian (SAS) AF: 0.00 AC: 0 AN: 4304

European-Finnish (FIN) AF: 0.000409 AC: 3 AN: 7326

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

European-Non Finnish (NFE) AF: 0.0000806 AC: 5 AN: 62052

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

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00838 Hom.: 18

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.14
Mutation Taster		=100/0	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;