19-45179662-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_212550.5(BLOC1S3):c.366C>T(p.His122=) 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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.160

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]

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]

ACMG classification

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 GnomAd at 19 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BLOC1S3	NM_212550.5	c.366C>T	p.His122=	synonymous_variant	2/2	ENST00000433642.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BLOC1S3	ENST00000433642.3	c.366C>T	p.His122=	synonymous_variant	2/2	2	NM_212550.5	P1
BLOC1S3	ENST00000587722.1	c.366C>T	p.His122=	synonymous_variant	1/1			P1
MARK4	ENST00000587566.5	c.-276-79327C>T		intron_variant		5
BLOC1S3	ENST00000592910.1			upstream_gene_variant		2

Frequencies

GnomAD3 genomes AF: 0.0156 AC: 2369 AN: 152062 Hom.: 19 Cov.: 32

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.: 18 AF XY: 0.0155 AC XY: 686 AN XY: 44376

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.: 31 AF XY: 0.0217 AC XY: 14061 AN XY: 647930

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.: 19 Cov.: 32 AF XY: 0.0153 AC XY: 1136 AN XY: 74388

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.: 0

Bravo AF: 0.0126

Asia WGS AF: 0.00497 AC: 18 AN: 3436

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 06, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 06, 2015	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). -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 26, 2020	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
Cadd	Benign	10
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

Other links and lift over

dbSNP: rs571269735; hg19: chr19-45682920;