chr6-15593088-G-GAAAAAAA

Variant names:

• chr6-15593088-G-GAAAAAAA
• rs199770715
• NM_032122.5:c.489-14_489-8dupTTTTTTT

Variant summary

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

The NM_032122.5(DTNBP1):​c.489-14_489-8dupTTTTTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000826 in 1,211,176 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 28)
  • Exomes 𝑓: 8.3e-7 (0 hom.)
• Consequence: DTNBP1 NM_032122.5 splice_region, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.127
• Publications: 0 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: Very rare variant in population databases, with high coverage

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.489-14_489-8dupTTTTTTT		splice_region intron	N/A	NP_115498.2
	DTNBP1	NM_001271668.2		c.438-14_438-8dupTTTTTTT		splice_region intron	N/A	NP_001258597.1
	DTNBP1	NM_001271669.2		c.384-14_384-8dupTTTTTTT		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.489-8_489-7insTTTTTTT		splice_region intron	N/A	ENSP00000341680.6
	DTNBP1	ENST00000622898.4	TSL:1	c.384-8_384-7insTTTTTTT		splice_region intron	N/A	ENSP00000481997.1
	DTNBP1	ENST00000338950.9	TSL:1	c.489-8_489-7insTTTTTTT		splice_region intron	N/A	ENSP00000344718.5

Frequencies

GnomAD3 genomes Cov.: 28

GnomAD4 exome AF: 8.26e-7 AC: 1 AN: 1211176 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 603406

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

African (AFR) AF: 0.00 AC: 0 AN: 26632

American (AMR) AF: 0.00 AC: 0 AN: 28930

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21998

East Asian (EAS) AF: 0.00 AC: 0 AN: 35390

South Asian (SAS) AF: 0.00 AC: 0 AN: 68926

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46046

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4826

European-Non Finnish (NFE) AF: 0.00000108 AC: 1 AN: 927854

Other (OTH) AF: 0.00 AC: 0 AN: 50574

⚠️ 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 Cov.: 28

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.13

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;