rs75792246

chr19-45179618-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_212550.5(BLOC1S3):c.322C>G(p.Leu108Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0407 in 1,475,054 control chromosomes in the GnomAD database, including 1,432 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. L108L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.029 (102 hom., cov: 32)
  • Exomes 𝑓: 0.042 (1330 hom.)
• Consequence: BLOC1S3 NM_212550.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.20

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008262664).
• BP6: Variant 19-45179618-C-G is Benign according to our data. Variant chr19-45179618-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 179946.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0291 (4425/152234) while in subpopulation NFE AF= 0.044 (2988/67978). AF 95% confidence interval is 0.0426. There are 102 homozygotes in gnomad4. There are 2131 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 102 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BLOC1S3	NM_212550.5	c.322C>G	p.Leu108Val	missense_variant	2/2	ENST00000433642.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BLOC1S3	ENST00000433642.3	c.322C>G	p.Leu108Val	missense_variant	2/2	2	NM_212550.5	P1
BLOC1S3	ENST00000587722.1	c.322C>G	p.Leu108Val	missense_variant	1/1			P1
MARK4	ENST00000587566.5	c.-276-79371C>G		intron_variant		5

Frequencies

GnomAD3 genomes AF: 0.0291 AC: 4425 AN: 152126 Hom.: 102 Cov.: 32

Gnomad AFR AF: 0.00719

Gnomad AMI AF: 0.0758

Gnomad AMR AF: 0.0221

Gnomad ASJ AF: 0.0115

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.00827

Gnomad FIN AF: 0.0570

Gnomad MID AF: 0.00321

Gnomad NFE AF: 0.0439

Gnomad OTH AF: 0.0216

GnomAD3 exomes AF: 0.0255 AC: 2078 AN: 81378 Hom.: 45 AF XY: 0.0251 AC XY: 1168 AN XY: 46468

Gnomad AFR exome AF: 0.00951

Gnomad AMR exome AF: 0.0176

Gnomad ASJ exome AF: 0.0144

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00937

Gnomad FIN exome AF: 0.0479

Gnomad NFE exome AF: 0.0414

Gnomad OTH exome AF: 0.0235

GnomAD4 exome AF: 0.0420 AC: 55597 AN: 1322820 Hom.: 1330 Cov.: 31 AF XY: 0.0411 AC XY: 26805 AN XY: 651658

Gnomad4 AFR exome AF: 0.00619

Gnomad4 AMR exome AF: 0.0182

Gnomad4 ASJ exome AF: 0.0142

Gnomad4 EAS exome AF: 0.0000341

Gnomad4 SAS exome AF: 0.00936

Gnomad4 FIN exome AF: 0.0472

Gnomad4 NFE exome AF: 0.0478

Gnomad4 OTH exome AF: 0.0372

GnomAD4 genome AF: 0.0291 AC: 4425 AN: 152234 Hom.: 102 Cov.: 32 AF XY: 0.0286 AC XY: 2131 AN XY: 74440

Gnomad4 AFR AF: 0.00714

Gnomad4 AMR AF: 0.0220

Gnomad4 ASJ AF: 0.0115

Gnomad4 EAS AF: 0.000579

Gnomad4 SAS AF: 0.00849

Gnomad4 FIN AF: 0.0570

Gnomad4 NFE AF: 0.0440

Gnomad4 OTH AF: 0.0213

Alfa AF: 0.0334 Hom.: 15

Bravo AF: 0.0259

ExAC AF: 0.00905 AC: 126

Asia WGS AF: 0.00408 AC: 14 AN: 3448

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Oct 21, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 20, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Dec 16, 2015	p.Leu108Val in exon 2 of BLOC1S3: This variant is not expected to have clinical significance because it has been identified in 1.63% (35/2144) of European chrom osomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org ; dbSNPrs75792246). -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 09, 2023	See Variant Classification Assertion Criteria. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.20
Cadd	Benign	22
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.77	D;D
Eigen	Uncertain	0.31
Eigen_PC	Benign	0.21
FATHMM_MKL	Benign	0.51	D
MetaRNN	Benign	0.0083	T;T
MetaSVM	Benign	-0.45	T
MutationAssessor	Benign	1.9	L;L
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-2.2	N;.
REVEL	Benign	0.11
Sift	Pathogenic	0.0	D;.
Sift4G	Benign	0.18	T;T
Polyphen		1.0	D;D
Vest4		0.31
MPC		2.0
ClinPred		0.029	T
GERP RS		3.7
Varity_R		0.53
gMVP		0.31

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: rs75792246; hg19: chr19-45682876; COSMIC: COSV99135287; COSMIC: COSV99135287;