15-45587446-G-A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_012388.4(BLOC1S6):c.3G>A(p.Met1?) variant causes a start lost change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: BLOC1S6 NM_012388.4 start_lost
• Clinical Significance: Uncertain significance criteria provided, single submitter U: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]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BLOC1S6	NM_012388.4	c.3G>A	p.Met1?	start_lost	1/5	ENST00000220531.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BLOC1S6	ENST00000220531.9	c.3G>A	p.Met1?	start_lost	1/5	1	NM_012388.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1425254 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 705704

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hermansky-Pudlak syndrome 9 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jun 06, 2021

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. This variant has not been reported in the literature in individuals with BLOC1S6-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change affects the initiator methionine of the BLOC1S6 mRNA. The next in-frame methionine is located at codon 98. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.14
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Benign	0.25	T;T;T
Eigen	Benign	0.069
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.90	D;D;D
M_CAP	Uncertain	0.18	D
MetaRNN	Pathogenic	0.96	D;D;D
MetaSVM	Benign	-0.79	T
MutationTaster	Benign	1.0	D;D;D;D;D
PROVEAN	Benign	-1.1	N;N;N
REVEL	Benign	0.20
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		0.030	B;.;.
Vest4		0.90
MutPred		0.86		Gain of glycosylation at S2 (P = 0.1073);Gain of glycosylation at S2 (P = 0.1073);Gain of glycosylation at S2 (P = 0.1073);
MVP		0.22
ClinPred		1.0	D
GERP RS		4.5
Varity_R		0.95

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs1242644356; hg19: chr15-45879644;