19-45179662-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -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

Publications

3 publications found

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 Gene-Disease associations (from GenCC):

neurodevelopmental disorder
Inheritance: AD Classification: LIMITED Submitted by: G2P

MARK4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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	Appris	UniProt
BLOC1S3	ENST00000433642.3 link	c.366C>T	p.His122His	synonymous_variant	Exon 2 of 2	2	NM_212550.5	ENSP00000393840.1		Q6QNY0

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

GnomAD2 exomes

AF:

0.0152

AC:

1179

AN:

77346

AF XY:

0.0155

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 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

African (AFR)

AF:

0.00267

AC:

AN:

26566

American (AMR)

AF:

0.00644

AC:

168

AN:

26082

Ashkenazi Jewish (ASJ)

AF:

0.00897

AC:

206

AN:

22978

East Asian (EAS)

AF:

0.0000347

AC:

AN:

28800

South Asian (SAS)

AF:

0.00985

AC:

709

AN:

71964

European-Finnish (FIN)

AF:

0.0343

AC:

1127

AN:

32864

Middle Eastern (MID)

AF:

0.00880

AC:

AN:

4318

European-Non Finnish (NFE)

AF:

0.0247

AC:

25882

AN:

1047688

Other (OTH)

AF:

0.0201

AC:

1097

AN:

54492

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1912

3824

5737

7649

9561

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

992

1984

2976

3968

4960

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0156

AC:

2367

AN:

152168

Hom.:

Cov.:

AF XY:

0.0153

AC XY:

1136

AN XY:

74388

show subpopulations

African (AFR)

AF:

0.00412

AC:

171

AN:

41540

American (AMR)

AF:

0.00694

AC:

106

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00923

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.00745

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.0329

AC:

348

AN:

10590

Middle Eastern (MID)

AF:

0.00342

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0237

AC:

1614

AN:

67966

Other (OTH)

AF:

0.0137

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

125

250

376

501

626

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

112

140

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

- -

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

May 26, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.47

CADD

Benign

(source)

DANN

Benign

0.96

PhyloP100

0.16

PromoterAI

0.66

Over-expression

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over