chr15-45587475-GGG-A

Variant names:

• chr15-45587475-GGG-A
• NM_012388.4:c.32_34delGGGinsA

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_012388.4(BLOC1S6):​c.32_34delGGGinsA​(p.Gly11AspfsTer20) variant causes a frameshift, missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. G11G) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: BLOC1S6 NM_012388.4 frameshift, missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 3.78
• Publications: 0 publications found

Genes affected

BLOC1S6 (HGNC:8549): (biogenesis of lysosomal organelles complex 1 subunit 6) The protein encoded by this gene may play a role in intracellular vesicle trafficking. It interacts with Syntaxin 13 which mediates intracellular membrane fusion. Mutations in this gene cause symptoms associated with Hermansky-Pudlak syndrome-9. Alternative splicing results in multiple transcript variants. A pseudogene related to this gene is located on the X chromosome. [provided by RefSeq, Aug 2015]

BLOC1S6 Gene-Disease associations (from GenCC):

• Hermansky-Pudlak syndrome 9

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae), ClinGen

ENSG00000260170 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 20 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 15-45587475-GGG-A is Pathogenic according to our data. Variant chr15-45587475-GGG-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 2584834.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012388.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BLOC1S6	NM_012388.4	MANE Select	c.32_34delGGGinsA	p.Gly11AspfsTer20	frameshift missense	Exon 1 of 5	NP_036520.1	Q9UL45-1
	BLOC1S6	NR_132351.2		n.97_99delGGGinsA		non_coding_transcript_exon	Exon 1 of 5
	BLOC1S6	NR_132352.2		n.97_99delGGGinsA		non_coding_transcript_exon	Exon 1 of 4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BLOC1S6	ENST00000220531.9	TSL:1 MANE Select	c.32_34delGGGinsA	p.Gly11AspfsTer20	frameshift missense	Exon 1 of 5	ENSP00000220531.4	Q9UL45-1
	ENSG00000260170	ENST00000564080.1	TSL:3	c.-68_-66delGGGinsA		5_prime_UTR	Exon 1 of 6	ENSP00000455047.1	H3BNX3
	BLOC1S6	ENST00000565216.5	TSL:3	c.32_34delGGGinsA	p.Gly11AspfsTer20	frameshift missense	Exon 1 of 5	ENSP00000456067.1	H3BR42

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Hermansky-Pudlak syndrome 9 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.8

Splicing

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

Other links and lift over

hg19: chr15-45879673;