6-8026405-CT-C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PVS1_Strong PM2 PP5

The NM_201280.3(BLOC1S5):c.345del(p.Val116SerfsTer19) 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 (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: BLOC1S5 NM_201280.3 frameshift
• Clinical Significance: Pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: -0.464

Genes affected

BLOC1S5 (HGNC:18561): (biogenesis of lysosomal organelles complex 1 subunit 5) This gene encodes a component of BLOC-1 (biogenesis of lysosome-related organelles complex 1). Components of this complex are involved in the biogenesis of organelles such as melanosomes and platelet-dense granules. A mouse model for Hermansky-Pudlak Syndrome is mutated in the murine version of this gene. Alternative splicing results in multiple transcript variants. Read-through transcription exists between this gene and the upstream EEF1E1 (eukaryotic translation elongation factor 1 epsilon 1) gene, as well as with the downstream TXNDC5 (thioredoxin domain containing 5) gene. [provided by RefSeq, Dec 2010]

BLOC1S5-TXNDC5 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.388 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 6-8026405-CT-C is Pathogenic according to our data. Variant chr6-8026405-CT-C is described in ClinVar as [Pathogenic]. Clinvar id is 870631.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BLOC1S5	NM_201280.3	c.345del	p.Val116SerfsTer19	frameshift_variant	4/5	ENST00000397457.7
BLOC1S5-TXNDC5	NR_037616.1	n.383del		non_coding_transcript_exon_variant	4/13
EEF1E1-BLOC1S5	NR_037618.1	n.691del		non_coding_transcript_exon_variant	6/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BLOC1S5	ENST00000397457.7	c.345del	p.Val116SerfsTer19	frameshift_variant	4/5	1	NM_201280.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: no assertion criteria provided

Submissions by phenotype

Hermansky-Pudlak syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Laboratoire de Genetique Moleculaire, Centre Hospitalier Universitaire de Bordeaux

Apr 09, 2020

One patient harbored a homozygous 1 bp deletion in exon 4 of BLOC1S5, NM_201280.2:c.345del p.(Val116Serf19*). ACMG classification is in favor of a pathogenic variant (PVS1, PS4, PM2). She had pigmented skin, blond hair and brown iris, and numerous pigmented naevi. She had mild ocular albinism including nystagmus, grade 1 retinal hypopigmentation, iris transillumination, optic nerve decussation anomalies on visual evoked potentials, strabismus, photophobia, and visual acuity of 6/10 on both eyes. The fovea was normal (Figure 2). Clinical report indicated important epistaxis, mostly in childhood, easy or unexplained bruising, menorrhagia improved by contraception, excessive blood loss after deliveries, surgery and dental extraction, as well as abdominal pain, dyspnea, and recurrent infections (pneumonia, herpes, conjunctivitis). These features suggested a syndromic form of albinism. Functionnal analysis of another LOF variant in BLOC1S5 are in favor of the involvment of BLOC1S5 in a new form of Hermansky-Pudlak Syndrome : HPS11. -

Hermansky-Pudlak syndrome 11 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 29, 2021

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs1763106978; hg19: chr6-8026638;