rs182286598

chr19-45179440-C-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_212550.5(BLOC1S3):c.144C>A(p.Arg48=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0156 in 1,525,754 control chromosomes in the GnomAD database, including 232 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. R48R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.010 (16 hom., cov: 32)
  • Exomes 𝑓: 0.016 (216 hom.)
• Consequence: BLOC1S3 NM_212550.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.333

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.3).
• BP6: Variant 19-45179440-C-A is Benign according to our data. Variant chr19-45179440-C-A is described in ClinVar as [Benign]. Clinvar id is 226463.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.333 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0103 (1572/152300) while in subpopulation NFE AF= 0.0177 (1205/68006). AF 95% confidence interval is 0.0169. There are 16 homozygotes in gnomad4. There are 718 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 16 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BLOC1S3	NM_212550.5	c.144C>A	p.Arg48=	synonymous_variant	2/2	ENST00000433642.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BLOC1S3	ENST00000433642.3	c.144C>A	p.Arg48=	synonymous_variant	2/2	2	NM_212550.5	P1
BLOC1S3	ENST00000587722.1	c.144C>A	p.Arg48=	synonymous_variant	1/1			P1
MARK4	ENST00000587566.5	c.-276-79549C>A		intron_variant		5

Frequencies

GnomAD3 genomes AF: 0.0103 AC: 1572 AN: 152188 Hom.: 16 Cov.: 32

Gnomad AFR AF: 0.00311

Gnomad AMI AF: 0.00877

Gnomad AMR AF: 0.00504

Gnomad ASJ AF: 0.00662

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00890

Gnomad FIN AF: 0.00659

Gnomad MID AF: 0.00637

Gnomad NFE AF: 0.0177

Gnomad OTH AF: 0.00718

GnomAD3 exomes AF: 0.0111 AC: 1445 AN: 129900 Hom.: 3 AF XY: 0.0109 AC XY: 787 AN XY: 72058

Gnomad AFR exome AF: 0.00333

Gnomad AMR exome AF: 0.00390

Gnomad ASJ exome AF: 0.00499

Gnomad EAS exome AF: 0.000200

Gnomad SAS exome AF: 0.00890

Gnomad FIN exome AF: 0.00922

Gnomad NFE exome AF: 0.0190

Gnomad OTH exome AF: 0.00931

GnomAD4 exome AF: 0.0162 AC: 22245 AN: 1373454 Hom.: 216 Cov.: 30 AF XY: 0.0160 AC XY: 10839 AN XY: 677560

Gnomad4 AFR exome AF: 0.00227

Gnomad4 AMR exome AF: 0.00401

Gnomad4 ASJ exome AF: 0.00558

Gnomad4 EAS exome AF: 0.000114

Gnomad4 SAS exome AF: 0.00967

Gnomad4 FIN exome AF: 0.0104

Gnomad4 NFE exome AF: 0.0186

Gnomad4 OTH exome AF: 0.0144

GnomAD4 genome AF: 0.0103 AC: 1572 AN: 152300 Hom.: 16 Cov.: 32 AF XY: 0.00964 AC XY: 718 AN XY: 74476

Gnomad4 AFR AF: 0.00310

Gnomad4 AMR AF: 0.00503

Gnomad4 ASJ AF: 0.00662

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00891

Gnomad4 FIN AF: 0.00659

Gnomad4 NFE AF: 0.0177

Gnomad4 OTH AF: 0.00710

Alfa AF: 0.0126 Hom.: 2

Bravo AF: 0.00941

Asia WGS AF: 0.00346 AC: 12 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 21, 2013	Arg48Arg in exon 2 of BLOC1S3: This variant is not expected to have clinical sig nificance because it does not alter an amino acid residue and is not located wit hin the splice consensus sequence. It has been identified in 1.4% (108/7706) of European American chromosomes from a broad population by the NHLBI Exome Sequenc ing Project (http://evs.gs.washington.edu/EVS; dbSNP rs182286598). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.30
Cadd	Benign	12
Dann	Benign	0.93

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: rs182286598; hg19: chr19-45682698; COSMIC: COSV50064998; COSMIC: COSV50064998;