19-45179313-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_212550.5(BLOC1S3):c.17G>A(p.Arg6His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000892 in 1,583,042 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00072 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00091 ( 0 hom. )

Consequence

BLOC1S3
NM_212550.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 1.99

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 Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.036010265).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BLOC1S3	NM_212550.5 linkuse as main transcript	c.17G>A	p.Arg6His	missense_variant	2/2	ENST00000433642.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
BLOC1S3	ENST00000433642.3 linkuse as main transcript	c.17G>A	p.Arg6His	missense_variant	2/2	2	NM_212550.5	P1
BLOC1S3	ENST00000587722.1 linkuse as main transcript	c.17G>A	p.Arg6His	missense_variant	1/1			P1
MARK4	ENST00000587566.5 linkuse as main transcript	c.-276-79676G>A		intron_variant		5

Frequencies

GnomAD3 genomes

AF:

0.000723

AC:

110

AN:

152246

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000458

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000482

AC:

103

AN:

213500

Hom.:

AF XY:

0.000440

AC XY:

AN XY:

118104

show subpopulations

Gnomad AFR exome

AF:

0.000165

Gnomad AMR exome

AF:

0.000222

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000358

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000924

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000910

AC:

1302

AN:

1430678

Hom.:

Cov.:

AF XY:

0.000897

AC XY:

638

AN XY:

711430

show subpopulations

Gnomad4 AFR exome

AF:

0.0000948

Gnomad4 AMR exome

AF:

0.000187

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000835

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00113

Gnomad4 OTH exome

AF:

0.000588

GnomAD4 genome

AF:

0.000722

AC:

110

AN:

152364

Hom.:

Cov.:

AF XY:

0.000752

AC XY:

AN XY:

74504

show subpopulations

Gnomad4 AFR

AF:

0.0000721

Gnomad4 AMR

AF:

0.000457

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.00105

Hom.:

Bravo

AF:

0.000691

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.000231

AC:

ESP6500EA

AF:

0.000589

AC:

ExAC

AF:

0.000457

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Nov 03, 2022	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 6 of the BLOC1S3 protein (p.Arg6His). This variant is present in population databases (rs145609489, gnomAD 0.09%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with BLOC1S3-related conditions. ClinVar contains an entry for this variant (Variation ID: 1369418). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Apr 11, 2023	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Uncertain

-0.080

Cadd

Benign

Dann

Uncertain

1.0

DEOGEN2

Benign

0.16

T;T

Eigen

Benign

0.12

Eigen_PC

Benign

0.095

FATHMM_MKL

Benign

0.50

M_CAP

Benign

0.018

MetaRNN

Benign

0.036

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.90

L;L

MutationTaster

Benign

0.92

N;N

PrimateAI

Pathogenic

0.84

PROVEAN

Benign

-1.4

N;.

REVEL

Benign

0.15

Sift

Pathogenic

0.0

D;.

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;D

Vest4

0.15

MVP

0.37

MPC

1.9

ClinPred

0.12

GERP RS

2.1

Varity_R

0.23

gMVP

0.24

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