15-45587475-GGG-A

Variant names:

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

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_Strong 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 (★).

• 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

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]

ENSG00000260170 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 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. Fraction of 0.938 CDS is truncated, and there are 1 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 id is 2584834.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BLOC1S6	NM_012388.4	c.32_34delGGGinsA	p.Gly11AspfsTer20	frameshift_variant, missense_variant	Exon 1 of 5	ENST00000220531.9	NP_036520.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BLOC1S6	ENST00000220531.9	c.32_34delGGGinsA	p.Gly11AspfsTer20	frameshift_variant, missense_variant	Exon 1 of 5	1	NM_012388.4	ENSP00000220531.4
ENSG00000260170	ENST00000564080	c.-68_-66delGGGinsA		5_prime_UTR_variant	Exon 1 of 6	3		ENSP00000455047.1

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

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hermansky-Pudlak syndrome 9 Pathogenic:1

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Neuberg Centre For Genomic Medicine, NCGM

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This variant causes a frameshift starting with codon Glycine 11, changes this amino acid to Aspartic acid residue, and creates a premature Stop codon at position 20 of the new reading frame, denoted p.Gly11AspfsTer20. The variant is novel (not in any individuals) in 1000 Genomes. Spasticity has not been reported previously with BLOC1S6. For these reasons, this variant has been classified as Likely pathogenic. . -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr15-45879673;