19-45179774-G-T

Position:

chr19-45179774-G-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_212550.5(BLOC1S3):c.478G>T(p.Val160Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00252 in 1,543,998 control chromosomes in the GnomAD database, including 8 homozygotes. 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0019 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0026 ( 7 hom. )

Consequence

BLOC1S3
NM_212550.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:4

Conservation

PhyloP100: 2.22

Variant links:

Genes affected

BLOC1S3 (HGNC:20914): (biogenesis of lysosomal organelles complex 1 subunit 3) This gene encodes a protein that is a component of the BLOC1 multi-subunit protein complex. This complex is necessary for the biogenesis of specialized organelles of the endosomal-lysosomal system, including platelet dense granules and melanosomes. Mutations in this gene cause Hermansky-Pudlak syndrome 8, a disease characterized by lysosomal storage defects, bleeding due to platelet storage pool deficiency, and oculocutaneous albinism. [provided by RefSeq, Jul 2008]

BLOC1S3 links:

MARK4 (HGNC:13538): (microtubule affinity regulating kinase 4) This gene encodes a member of the microtubule affinity-regulating kinase family. These protein kinases phosphorylate microtubule-associated proteins and regulate the transition between stable and dynamic microtubules. The encoded protein is associated with the centrosome throughout mitosis and may be involved in cell cycle control. Expression of this gene is a potential marker for cancer, and the encoded protein may also play a role in Alzheimer's disease. Pseudogenes of this gene are located on both the short and long arm of chromosome 3. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Dec 2010]

MARK4 links:

BLOC1S3 (HGNC:):

BLOC1S3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.007274896).

BP6

Variant 19-45179774-G-T is Benign according to our data. Variant chr19-45179774-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 290104.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=2}. Variant chr19-45179774-G-T is described in Lovd as [Likely_benign].

BS2

High Homozygotes in GnomAdExome4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BLOC1S3	NM_212550.5 linkuse as main transcript	c.478G>T	p.Val160Leu	missense_variant	2/2	ENST00000433642.3	NP_997715.1	Q6QNY0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BLOC1S3	ENST00000433642.3 linkuse as main transcript	c.478G>T	p.Val160Leu	missense_variant	2/2	2	NM_212550.5	ENSP00000393840.1		Q6QNY0

Frequencies

GnomAD3 genomes

AF:

0.00195

AC:

296

AN:

152114

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000796

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00354

Gnomad ASJ

AF:

0.00259

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00318

Gnomad NFE

AF:

0.00281

Gnomad OTH

AF:

0.00383

GnomAD3 exomes

AF:

0.00167

AC:

245

AN:

146848

Hom.:

AF XY:

0.00162

AC XY:

135

AN XY:

83322

show subpopulations

Gnomad AFR exome

AF:

0.000216

Gnomad AMR exome

AF:

0.00176

Gnomad ASJ exome

AF:

0.00347

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000210

Gnomad FIN exome

AF:

0.000577

Gnomad NFE exome

AF:

0.00250

Gnomad OTH exome

AF:

0.00210

GnomAD4 exome

AF:

0.00259

AC:

3600

AN:

1391774

Hom.:

Cov.:

AF XY:

0.00253

AC XY:

1742

AN XY:

689776

show subpopulations

Gnomad4 AFR exome

AF:

0.000415

Gnomad4 AMR exome

AF:

0.00209

Gnomad4 ASJ exome

AF:

0.00350

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000211

Gnomad4 FIN exome

AF:

0.000391

Gnomad4 NFE exome

AF:

0.00297

Gnomad4 OTH exome

AF:

0.00232

GnomAD4 genome

AF:

0.00194

AC:

296

AN:

152224

Hom.:

Cov.:

AF XY:

0.00203

AC XY:

151

AN XY:

74426

show subpopulations

Gnomad4 AFR

AF:

0.000794

Gnomad4 AMR

AF:

0.00353

Gnomad4 ASJ

AF:

0.00259

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00281

Gnomad4 OTH

AF:

0.00379

Alfa

AF:

0.000648

Hom.:

Bravo

AF:

0.00229

ExAC

AF:

0.00121

AC:

134

Asia WGS

AF:

0.000578

AC:

AN:

3474

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Oct 10, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Nov 03, 2023	BP4, PM1 -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 21, 2021

The c.478G>T (p.V160L) alteration is located in exon 2 (coding exon 1) of the BLOC1S3 gene. This alteration results from a G to T substitution at nucleotide position 478, causing the valine (V) at amino acid position 160 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

BLOC1S3-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 08, 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). -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Sep 20, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.28

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.33

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Benign

0.16

T;T;T

Eigen

Benign

-0.32

Eigen_PC

Benign

-0.23

FATHMM_MKL

Benign

0.57

LIST_S2

Benign

0.52

.;T;T

MetaRNN

Benign

0.0073

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.55

N;N;.

PrimateAI

Pathogenic

0.96

PROVEAN

Benign

-0.21

N;.;.

REVEL

Benign

0.074

Sift

Benign

0.53

T;.;.

Sift4G

Benign

0.35

T;T;T

Polyphen

0.64

P;P;.

Vest4

0.17

MutPred

0.22

Gain of disorder (P = 0.1041);Gain of disorder (P = 0.1041);.;

MVP

0.14

MPC

0.98

ClinPred

0.015

GERP RS

2.2

Varity_R

0.070

gMVP

0.23

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