19-45179662-C-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_212550.5(BLOC1S3):c.366C>T(p.His122His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0216 in 1,467,920 control chromosomes in the GnomAD database, including 411 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.016 ( 19 hom., cov: 32)

Exomes 𝑓: 0.022 ( 392 hom. )

Consequence

BLOC1S3
NM_212550.5 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.160

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.47).

BP6

Variant 19-45179662-C-T is Benign according to our data. Variant chr19-45179662-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 162792.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.16 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0156 (2367/152168) while in subpopulation NFE AF= 0.0237 (1614/67966). AF 95% confidence interval is 0.0228. There are 19 homozygotes in gnomad4. There are 1136 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 19 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BLOC1S3	NM_212550.5 link	c.366C>T	p.His122His	synonymous_variant	Exon 2 of 2	ENST00000433642.3	NP_997715.1	Q6QNY0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
BLOC1S3	ENST00000433642.3 link	c.366C>T	p.His122His	synonymous_variant	Exon 2 of 2	2	NM_212550.5	ENSP00000393840.1	Q6QNY0
BLOC1S3	ENST00000587722.1 link	c.366C>T	p.His122His	synonymous_variant	Exon 1 of 1	6		ENSP00000468281.1	Q6QNY0
MARK4	ENST00000587566.5 link	c.-276-79327C>T		intron_variant	Intron 1 of 6	5		ENSP00000465414.1	K7EK17
BLOC1S3	ENST00000592910.1 link	c.-7C>T		upstream_gene_variant		2		ENSP00000466798.1	K7EN58

Frequencies

GnomAD3 genomes

AF:

0.0156

AC:

2369

AN:

152062

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00413

Gnomad AMI

AF:

0.0329

Gnomad AMR

AF:

0.00708

Gnomad ASJ

AF:

0.00923

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00744

Gnomad FIN

AF:

0.0329

Gnomad MID

AF:

0.00318

Gnomad NFE

AF:

0.0237

Gnomad OTH

AF:

0.0139

GnomAD3 exomes

AF:

0.0152

AC:

1179

AN:

77346

Hom.:

AF XY:

0.0155

AC XY:

686

AN XY:

44376

show subpopulations

Gnomad AFR exome

AF:

0.00346

Gnomad AMR exome

AF:

0.00462

Gnomad ASJ exome

AF:

0.00736

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0104

Gnomad FIN exome

AF:

0.0393

Gnomad NFE exome

AF:

0.0235

Gnomad OTH exome

AF:

0.0143

GnomAD4 exome

AF:

0.0223

AC:

29299

AN:

1315752

Hom.:

392

Cov.:

AF XY:

0.0217

AC XY:

14061

AN XY:

647930

show subpopulations

Gnomad4 AFR exome

AF:

0.00267

Gnomad4 AMR exome

AF:

0.00644

Gnomad4 ASJ exome

AF:

0.00897

Gnomad4 EAS exome

AF:

0.0000347

Gnomad4 SAS exome

AF:

0.00985

Gnomad4 FIN exome

AF:

0.0343

Gnomad4 NFE exome

AF:

0.0247

Gnomad4 OTH exome

AF:

0.0201

GnomAD4 genome

AF:

0.0156

AC:

2367

AN:

152168

Hom.:

Cov.:

AF XY:

0.0153

AC XY:

1136

AN XY:

74388

show subpopulations

Gnomad4 AFR

AF:

0.00412

Gnomad4 AMR

AF:

0.00694

Gnomad4 ASJ

AF:

0.00923

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00745

Gnomad4 FIN

AF:

0.0329

Gnomad4 NFE

AF:

0.0237

Gnomad4 OTH

AF:

0.0137

Alfa

AF:

0.00715

Hom.:

Bravo

AF:

0.0126

Asia WGS

AF:

0.00497

AC:

AN:

3436

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Aug 06, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.His122His in exon 2 of BLOC1S3: This variant is not expected to have clinical significance because it does not alter an amino acid residue and is not located within the splice consensus sequence. It has been identified in 1.7% (35/2034) o f European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.br oadinstitute.org; dbSNP rs571269735). -

Aug 06, 2018

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 26, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.47

CADD

Benign

DANN

Benign

0.96

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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