15-45587490-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_012388.4(BLOC1S6):c.47C>T(p.Pro16Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000631 in 1,585,462 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: BLOC1S6 NM_012388.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.964

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.061819255).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BLOC1S6	NM_012388.4	c.47C>T	p.Pro16Leu	missense_variant	1/5	ENST00000220531.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BLOC1S6	ENST00000220531.9	c.47C>T	p.Pro16Leu	missense_variant	1/5	1	NM_012388.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000525 AC: 8 AN: 152270 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000964

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000140 AC: 2 AN: 1433192 Hom.: 0 Cov.: 31 AF XY: 0.00000141 AC XY: 1 AN XY: 710434

Gnomad4 AFR exome AF: 0.0000305

Gnomad4 AMR exome AF: 0.0000244

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 AF: 0.0000525 AC: 8 AN: 152270 Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3 AN XY: 74392

Gnomad4 AFR AF: 0.0000964

Gnomad4 AMR AF: 0.000262

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000329 Hom.: 0

Bravo AF: 0.0000453

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hermansky-Pudlak syndrome 9 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jul 18, 2022	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 16 of the BLOC1S6 protein (p.Pro16Leu). 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. ClinVar contains an entry for this variant (Variation ID: 1042331). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The leucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	New York Genome Center	Mar 12, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.40
Cadd	Benign	15
Dann	Uncertain	0.98
DEOGEN2	Benign	0.26	T;T;T
Eigen	Benign	-0.89
Eigen_PC	Benign	-0.89
FATHMM_MKL	Benign	0.058	N
LIST_S2	Benign	0.75	T;T;T
M_CAP	Benign	0.0028	T
MetaRNN	Benign	0.062	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.0	M;.;.
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.84	N;D;N
REVEL	Benign	0.050
Sift	Benign	0.14	T;T;D
Sift4G	Benign	0.46	T;T;D
Polyphen		0.0	B;.;.
Vest4		0.11
MVP		0.12
MPC		0.41
ClinPred		0.069	T
GERP RS		1.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.036

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: rs1042113102; hg19: chr15-45879688;