NM_012388.4:c.7_22dupGTCCCTGGGCCGTCGT

Variant names:

• chr15-45587447-A-AGTGTCCCTGGGCCGTC
• NM_012388.4:c.7_22dupGTCCCTGGGCCGTCGT

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.7_22dupGTCCCTGGGCCGTCGT​(p.Ser8CysfsTer29) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: BLOC1S6 NM_012388.4 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 0.314

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 0.956 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 15-45587447-A-AGTGTCCCTGGGCCGTC is Pathogenic according to our data. Variant chr15-45587447-A-AGTGTCCCTGGGCCGTC is described in ClinVar as [Pathogenic]. Clinvar id is 2875941.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.7_22dupGTCCCTGGGCCGTCGT	p.Ser8CysfsTer29	frameshift_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.7_22dupGTCCCTGGGCCGTCGT	p.Ser8CysfsTer29	frameshift_variant	Exon 1 of 5	1	NM_012388.4	ENSP00000220531.4
ENSG00000260170	ENST00000564080	c.-93_-78dupGTCCCTGGGCCGTCGT		5_prime_UTR_variant	Exon 1 of 6	3		ENSP00000455047.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hermansky-Pudlak syndrome 9 Pathogenic:1

Apr 17, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Ser8Cysfs*29) in the BLOC1S6 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BLOC1S6 are known to be pathogenic (PMID: 10610180, 21665000, 22461475). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with BLOC1S6-related conditions. For these reasons, this variant has been classified as 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: chr15-45879645;