6-8026405-CT-C

Variant names:

• chr6-8026405-CT-C
• rs1763106978
• NM_201280.3:c.345delA

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.345delA​(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]

EEF1E1-BLOC1S5 (HGNC:49187): (EEF1E1-BLOC1S5 readthrough (NMD candidate)) This locus represents naturally occurring read-through transcription between the neighboring EEF1E1 (eukaryotic translation elongation factor 1 epsilon 1) and MUTED (muted homolog) genes on chromosome 6. The read-through transcript is a candidate for nonsense-mediated mRNA decay (NMD) and is unlikely to produce a protein product. [provided by RefSeq, Dec 2010]

BLOC1S5-TXNDC5 (HGNC:42001): (BLOC1S5-TXNDC5 readthrough (NMD candidate)) This locus represents naturally occurring read-through transcription between the neighboring MUTED (muted homolog) and TXNDC5 (thioredoxin domain containing 5) genes on chromosome 6. The read-through transcript is a candidate for nonsense-mediated mRNA decay (NMD) and is unlikely to produce a protein product. [provided by RefSeq, Dec 2010]

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 rank	MANE	Protein	UniProt
BLOC1S5	NM_201280.3	c.345delA	p.Val116SerfsTer19	frameshift_variant	Exon 4 of 5	ENST00000397457.7	NP_958437.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BLOC1S5	ENST00000397457.7	c.345delA	p.Val116SerfsTer19	frameshift_variant	Exon 4 of 5	1	NM_201280.3	ENSP00000380598.2
EEF1E1-BLOC1S5	ENST00000397456.2	n.*161delA		non_coding_transcript_exon_variant	Exon 6 of 7	3		ENSP00000380597.2
BLOC1S5-TXNDC5	ENST00000439343.2	n.333delA		non_coding_transcript_exon_variant	Exon 4 of 13	2		ENSP00000454697.1
EEF1E1-BLOC1S5	ENST00000397456.2	n.*161delA		3_prime_UTR_variant	Exon 6 of 7	3		ENSP00000380597.2

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

Apr 09, 2020

Laboratoire de Génétique Moléculaire, CHU Bordeaux

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Jan 29, 2021

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

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;