rs546645333

Positions:

chr19-45179635-G-A

Variant summary

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

The NM_212550.5(BLOC1S3):c.339G>A(p.Leu113Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00884 in 1,472,916 control chromosomes in the GnomAD database, including 75 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0070 ( 6 hom., cov: 32)

Exomes 𝑓: 0.0091 ( 69 hom. )

Consequence

BLOC1S3
NM_212550.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 2.63

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=-0.64).

BP6

Variant 19-45179635-G-A is Benign according to our data. Variant chr19-45179635-G-A is described in ClinVar as [Benign]. Clinvar id is 226464.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=2.63 with no splicing effect.

BS1

Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00905 (11956/1320688) while in subpopulation MID AF= 0.0267 (114/4274). AF 95% confidence interval is 0.0227. There are 69 homozygotes in gnomad4_exome. There are 5865 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BLOC1S3	NM_212550.5 link	c.339G>A	p.Leu113Leu	synonymous_variant	2/2	ENST00000433642.3	NP_997715.1	Q6QNY0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
BLOC1S3	ENST00000433642.3 link	c.339G>A	p.Leu113Leu	synonymous_variant	2/2	2	NM_212550.5	ENSP00000393840.1	Q6QNY0
BLOC1S3	ENST00000587722.1 link	c.339G>A	p.Leu113Leu	synonymous_variant	1/1	6		ENSP00000468281.1	Q6QNY0
MARK4	ENST00000587566.5 link	c.-276-79354G>A		intron_variant		5		ENSP00000465414.1	K7EK17
BLOC1S3	ENST00000592910.1 link	c.-34G>A		upstream_gene_variant		2		ENSP00000466798.1	K7EN58

Frequencies

GnomAD3 genomes

AF:

0.00699

AC:

1063

AN:

152120

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00200

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00989

Gnomad ASJ

AF:

0.0130

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00248

Gnomad FIN

AF:

0.00614

Gnomad MID

AF:

0.0159

Gnomad NFE

AF:

0.0100

Gnomad OTH

AF:

0.00909

GnomAD3 exomes

AF:

0.00901

AC:

720

AN:

79878

Hom.:

AF XY:

0.00805

AC XY:

368

AN XY:

45722

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0105

Gnomad ASJ exome

AF:

0.0126

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00450

Gnomad FIN exome

AF:

0.00480

Gnomad NFE exome

AF:

0.0114

Gnomad OTH exome

AF:

0.0180

GnomAD4 exome

AF:

0.00905

AC:

11956

AN:

1320688

Hom.:

Cov.:

AF XY:

0.00902

AC XY:

5865

AN XY:

650508

show subpopulations

Gnomad4 AFR exome

AF:

0.00176

Gnomad4 AMR exome

AF:

0.0110

Gnomad4 ASJ exome

AF:

0.0123

Gnomad4 EAS exome

AF:

0.0000343

Gnomad4 SAS exome

AF:

0.00443

Gnomad4 FIN exome

AF:

0.00510

Gnomad4 NFE exome

AF:

0.00972

Gnomad4 OTH exome

AF:

0.00939

GnomAD4 genome

AF:

0.00699

AC:

1064

AN:

152228

Hom.:

Cov.:

AF XY:

0.00677

AC XY:

504

AN XY:

74442

show subpopulations

Gnomad4 AFR

AF:

0.00200

Gnomad4 AMR

AF:

0.00988

Gnomad4 ASJ

AF:

0.0130

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00269

Gnomad4 FIN

AF:

0.00614

Gnomad4 NFE

AF:

0.0100

Gnomad4 OTH

AF:

0.00900

Alfa

AF:

0.00773

Hom.:

Bravo

AF:

0.00743

Asia WGS

AF:

0.000877

AC:

AN:

3436

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 12, 2015	p.Leu113Leu 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 1.4% (29/2132) o f European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.br oadinstitute.org; dbSNP rs546645333). -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Mar 30, 2020	- -

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.64

CADD

Benign

7.1

DANN

Benign

0.96

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