6-8054272-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_201280.3(BLOC1S5):c.195+8262A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00312 in 452,292 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0075 (11 hom., cov: 33)
  • Exomes 𝑓: 0.00087 (3 hom.)
• Consequence: BLOC1S5 NM_201280.3 intron
• Scores: Splicing: ADA: 0.00001157
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.263

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 6-8054272-T-C is Benign according to our data. Variant chr6-8054272-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 3056960.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00755 (1149/152270) while in subpopulation AFR AF= 0.0262 (1087/41530). AF 95% confidence interval is 0.0249. There are 11 homozygotes in gnomad4. There are 546 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BLOC1S5	NM_201280.3	c.195+8262A>G		intron_variant		ENST00000397457.7
BLOC1S5-TXNDC5	NR_037616.1	n.233+8262A>G		intron_variant, non_coding_transcript_variant
EEF1E1-BLOC1S5	NR_037618.1	n.541+8262A>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BLOC1S5	ENST00000397457.7	c.195+8262A>G		intron_variant		1	NM_201280.3	P1
BLOC1S5	ENST00000244777.6	c.195+8262A>G		intron_variant, NMD_transcript_variant		1
BLOC1S5	ENST00000627748.2	c.*89A>G		splice_region_variant, 3_prime_UTR_variant, NMD_transcript_variant	3/6	1
BLOC1S5	ENST00000543936.7	c.195+8262A>G		intron_variant		2

Frequencies

GnomAD3 genomes AF: 0.00747 AC: 1137 AN: 152152 Hom.: 9 Cov.: 33

Gnomad AFR AF: 0.0260

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00288

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00430

GnomAD3 exomes AF: 0.00140 AC: 183 AN: 130398 Hom.: 1 AF XY: 0.00115 AC XY: 82 AN XY: 71346

Gnomad AFR exome AF: 0.0239

Gnomad AMR exome AF: 0.000961

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000462

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000963

Gnomad OTH exome AF: 0.00125

GnomAD4 exome AF: 0.000873 AC: 262 AN: 300022 Hom.: 3 Cov.: 0 AF XY: 0.000689 AC XY: 118 AN XY: 171280

Gnomad4 AFR exome AF: 0.0234

Gnomad4 AMR exome AF: 0.000928

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000851

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000317

Gnomad4 OTH exome AF: 0.00214

GnomAD4 genome AF: 0.00755 AC: 1149 AN: 152270 Hom.: 11 Cov.: 33 AF XY: 0.00733 AC XY: 546 AN XY: 74454

Gnomad4 AFR AF: 0.0262

Gnomad4 AMR AF: 0.00288

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.00425

Alfa AF: 0.00322 Hom.: 0

Bravo AF: 0.00846

Asia WGS AF: 0.00318 AC: 11 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

BLOC1S5-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 26, 2021

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
Cadd	Benign	5.8
Dann	Benign	0.46

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000012
dbscSNV1_RF	Benign	0.0060
SpliceAI score (max)		0.0		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: rs75648425; hg19: chr6-8054505;