rs145762743

chr15-45587477-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS1

The NM_012388.4(BLOC1S6):c.34G>A(p.Ala12Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000514 in 1,584,574 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A12A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0029 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00026 (1 hom.)
• Consequence: BLOC1S6 NM_012388.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.292

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 Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0027925074).
• BP6: Variant 15-45587477-G-A is Benign according to our data. Variant chr15-45587477-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 434516.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00289 (441/152368) while in subpopulation AFR AF= 0.0101 (418/41580). AF 95% confidence interval is 0.00926. There are 1 homozygotes in gnomad4. There are 214 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BLOC1S6	NM_012388.4	c.34G>A	p.Ala12Thr	missense_variant	1/5	ENST00000220531.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BLOC1S6	ENST00000220531.9	c.34G>A	p.Ala12Thr	missense_variant	1/5	1	NM_012388.4	P1

Frequencies

GnomAD3 genomes AF: 0.00287 AC: 437 AN: 152250 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00999

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000916

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.000743 AC: 149 AN: 200578 Hom.: 0 AF XY: 0.000629 AC XY: 68 AN XY: 108098

Gnomad AFR exome AF: 0.0106

Gnomad AMR exome AF: 0.000466

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000346

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000195

GnomAD4 exome AF: 0.000261 AC: 374 AN: 1432206 Hom.: 1 Cov.: 31 AF XY: 0.000238 AC XY: 169 AN XY: 709750

Gnomad4 AFR exome AF: 0.00943

Gnomad4 AMR exome AF: 0.000366

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000122

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000273

Gnomad4 OTH exome AF: 0.000625

GnomAD4 genome AF: 0.00289 AC: 441 AN: 152368 Hom.: 1 Cov.: 33 AF XY: 0.00287 AC XY: 214 AN XY: 74512

Gnomad4 AFR AF: 0.0101

Gnomad4 AMR AF: 0.000915

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00236

Alfa AF: 0.000963 Hom.: 0

Bravo AF: 0.00317

ESP6500AA AF: 0.0105 AC: 46

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000966 AC: 116

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Nov 10, 2015

- -

Hermansky-Pudlak syndrome 9 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Feb 01, 2023

BLOC1S6: BP4, BS1 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.65
Cadd	Benign	11
Dann	Uncertain	0.99
DEOGEN2	Benign	0.20	T;T;T
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.62
FATHMM_MKL	Benign	0.37	N
LIST_S2	Benign	0.74	T;T;T
MetaRNN	Benign	0.0028	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.69	N;.;.
MutationTaster	Benign	1.0	D;D;N;N;N
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.59	N;N;N
REVEL	Benign	0.051
Sift	Benign	0.16	T;T;T
Sift4G	Benign	0.69	T;T;T
Polyphen		0.0040	B;.;.
Vest4		0.062
MVP		0.061
MPC		0.39
ClinPred		0.013	T
GERP RS		3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.048

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: rs145762743; hg19: chr15-45879675; COSMIC: COSV99076468; COSMIC: COSV99076468;