19-45179348-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_212550.5(BLOC1S3):c.52G>A(p.Val18Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000836 in 1,434,914 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000084 (0 hom.)
• Consequence: BLOC1S3 NM_212550.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.46

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.39903027).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BLOC1S3	NM_212550.5	c.52G>A	p.Val18Met	missense_variant	2/2	ENST00000433642.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BLOC1S3	ENST00000433642.3	c.52G>A	p.Val18Met	missense_variant	2/2	2	NM_212550.5	P1
BLOC1S3	ENST00000587722.1	c.52G>A	p.Val18Met	missense_variant	1/1			P1
MARK4	ENST00000587566.5	c.-276-79641G>A		intron_variant		5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000183 AC: 4 AN: 218546 Hom.: 0 AF XY: 0.0000166 AC XY: 2 AN XY: 120744

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000389

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000836 AC: 12 AN: 1434914 Hom.: 0 Cov.: 30 AF XY: 0.00000700 AC XY: 5 AN XY: 713892

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000994

Gnomad4 OTH exome AF: 0.0000168

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ExAC AF: 0.00000828 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Feb 24, 2022

This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 18 of the BLOC1S3 protein (p.Val18Met). This variant is present in population databases (rs767819779, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with BLOC1S3-related conditions. 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: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C15"). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.62
BayesDel_addAF	Benign	-0.034	T
BayesDel_noAF	Benign	-0.21
Cadd	Uncertain	24
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.79	D;D
Eigen	Uncertain	0.24
Eigen_PC	Benign	0.11
FATHMM_MKL	Benign	0.67	D
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.40	T;T
MetaSVM	Benign	-0.40	T
MutationAssessor	Benign	1.9	L;L
MutationTaster	Benign	0.90	D;D
PrimateAI	Pathogenic	0.91	D
PROVEAN	Uncertain	-2.8	D;.
REVEL	Benign	0.16
Sift	Uncertain	0.0030	D;.
Sift4G	Benign	0.063	T;T
Polyphen		1.0	D;D
Vest4		0.37
MutPred		0.19		Loss of MoRF binding (P = 0.1289);Loss of MoRF binding (P = 0.1289);
MVP		0.30
MPC		1.7
ClinPred		0.86	D
GERP RS		3.5
Varity_R		0.42
gMVP		0.36

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: rs767819779; hg19: chr19-45682606;