15-45587522-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBS1_Supporting

The NM_012388.4(BLOC1S6):c.79C>T(p.Pro27Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000502 in 1,572,774 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00028 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000026 ( 0 hom. )

Consequence

BLOC1S6
NM_012388.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 1.71

Variant links:

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]

BLOC1S6 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.024336427).

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000276 (42/152362) while in subpopulation AFR AF= 0.000962 (40/41594). AF 95% confidence interval is 0.000725. There are 0 homozygotes in gnomad4. There are 15 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BLOC1S6	NM_012388.4 linkuse as main transcript	c.79C>T	p.Pro27Ser	missense_variant	1/5	ENST00000220531.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BLOC1S6	ENST00000220531.9 linkuse as main transcript	c.79C>T	p.Pro27Ser	missense_variant	1/5	1	NM_012388.4	P1	Q9UL45-1

Frequencies

GnomAD3 genomes

AF:

0.000276

AC:

AN:

152244

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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

GnomAD3 exomes

AF:

0.0000331

AC:

AN:

181366

Hom.:

AF XY:

0.0000409

AC XY:

AN XY:

97816

show subpopulations

Gnomad AFR exome

AF:

0.000588

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000260

AC:

AN:

1420412

Hom.:

Cov.:

AF XY:

0.0000256

AC XY:

AN XY:

703214

show subpopulations

Gnomad4 AFR exome

AF:

0.00108

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:

0.0000340

GnomAD4 genome

AF:

0.000276

AC:

AN:

152362

Hom.:

Cov.:

AF XY:

0.000201

AC XY:

AN XY:

74502

show subpopulations

Gnomad4 AFR

AF:

0.000962

Gnomad4 AMR

AF:

0.000131

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:

0.000201

Hom.:

Bravo

AF:

0.000257

ESP6500AA

AF:

0.00115

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000421

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hermansky-Pudlak syndrome 9

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 31, 2022

This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 27 of the BLOC1S6 protein (p.Pro27Ser). This variant is present in population databases (rs138284359, gnomAD 0.07%). 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: 565888). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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. -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 18, 2023

The c.79C>T (p.P27S) alteration is located in exon 1 (coding exon 1) of the BLOC1S6 gene. This alteration results from a C to T substitution at nucleotide position 79, causing the proline (P) at amino acid position 27 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.42

Cadd

Benign

Dann

Benign

0.90

DEOGEN2

Benign

0.21

T;T;T

Eigen

Benign

-0.71

Eigen_PC

Benign

-0.65

FATHMM_MKL

Benign

0.14

LIST_S2

Benign

0.73

T;T;T

M_CAP

Benign

0.0097

MetaRNN

Benign

0.024

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.6

L;.;.

MutationTaster

Benign

1.0

D;D;N;N;N

PrimateAI

Benign

0.35

PROVEAN

Benign

-0.11

N;N;N

REVEL

Benign

0.055

Sift

Benign

0.36

T;T;T

Sift4G

Benign

0.50

T;T;T

Polyphen

0.013

B;.;.

Vest4

0.11

MVP

0.11

MPC

0.41

ClinPred

0.024

GERP RS

3.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.7

Varity_R

0.033

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over