rs199770715

Variant names:

• chr6-15593088-GAAAAA-G
• rs199770715
• NM_032122.5:c.489-12_489-8delTTTTT

Your query was ambiguous. Multiple possible variants found:

• chr6-15593088-GAAAAA-G
• chr6-15593088-GAAAAA-GA
• chr6-15593088-GAAAAA-GAA
• chr6-15593088-GAAAAA-GAAA
• chr6-15593088-GAAAAA-GAAAA
• chr6-15593088-GAAAAA-GAAAAAA
• chr6-15593088-GAAAAA-GAAAAAAA
• chr6-15593088-GAAAAA-GAAAAAAAA
• chr6-15593088-GAAAAA-GAAAAAAAAA
• chr6-15593088-GAAAAA-GAAAAAAAAAA
• chr6-15593088-GAAAAA-GAAAAAAAAAAAA

Variant summary

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

The NM_032122.5(DTNBP1):​c.489-12_489-8delTTTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000134 in 1,346,918 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000015 (0 hom., cov: 28)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: DTNBP1 NM_032122.5 splice_region, intron
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.55
• 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: 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.489-12_489-8delTTTTT		splice_region intron	N/A	NP_115498.2
	DTNBP1	NM_001271668.2		c.438-12_438-8delTTTTT		splice_region intron	N/A	NP_001258597.1
	DTNBP1	NM_001271669.2		c.384-12_384-8delTTTTT		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.489-12_489-8delTTTTT		splice_region intron	N/A	ENSP00000341680.6
	DTNBP1	ENST00000622898.4	TSL:1	c.384-12_384-8delTTTTT		splice_region intron	N/A	ENSP00000481997.1
	DTNBP1	ENST00000338950.9	TSL:1	c.489-12_489-8delTTTTT		splice_region intron	N/A	ENSP00000344718.5

Frequencies

GnomAD3 genomes AF: 0.0000147 AC: 2 AN: 135862 Hom.: 0 Cov.: 28

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000322

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000132 AC: 16 AN: 1211056 Hom.: 0 AF XY: 0.0000133 AC XY: 8 AN XY: 603352

⚠️ 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: 26630

American (AMR) AF: 0.0000346 AC: 1 AN: 28928

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

East Asian (EAS) AF: 0.0000283 AC: 1 AN: 35388

South Asian (SAS) AF: 0.0000145 AC: 1 AN: 68910

European-Finnish (FIN) AF: 0.0000434 AC: 2 AN: 46038

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4824

European-Non Finnish (NFE) AF: 0.00000970 AC: 9 AN: 927766

Other (OTH) AF: 0.0000395 AC: 2 AN: 50574

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00203225), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000147 AC: 2 AN: 135862 Hom.: 0 Cov.: 28 AF XY: 0.0000305 AC XY: 2 AN XY: 65468

African (AFR) AF: 0.00 AC: 0 AN: 37426

American (AMR) AF: 0.00 AC: 0 AN: 13580

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 4858

South Asian (SAS) AF: 0.00 AC: 0 AN: 4318

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 7348

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000322 AC: 2 AN: 62092

Other (OTH) AF: 0.00 AC: 0 AN: 1862

Alfa AF: 0.00 Hom.: 18

Bravo AF: 0.0000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

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 v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.5

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;