rs201502372

Variant names:

• chr19-45179774-G-A
• rs201502372
• NM_212550.5:c.478G>A

Your query was ambiguous. Multiple possible variants found:

• chr19-45179774-G-A
• chr19-45179774-G-C
• chr19-45179774-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_212550.5(BLOC1S3):​c.478G>A​(p.Val160Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000719 in 1,391,778 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V160L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: BLOC1S3 NM_212550.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.22
• Publications: 7 publications found

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]

MARK4 Gene-Disease associations (from GenCC):

• neurodevelopmental disorder

  Inheritance: AD Classification: LIMITED Submitted by: G2P

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.204371).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BLOC1S3	NM_212550.5	c.478G>A	p.Val160Met	missense_variant	Exon 2 of 2	ENST00000433642.3	NP_997715.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BLOC1S3	ENST00000433642.3	c.478G>A	p.Val160Met	missense_variant	Exon 2 of 2	2	NM_212550.5	ENSP00000393840.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.19e-7 AC: 1 AN: 1391778 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 689778

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 28912

American (AMR) AF: 0.00 AC: 0 AN: 35812

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24292

East Asian (EAS) AF: 0.00 AC: 0 AN: 33948

South Asian (SAS) AF: 0.00 AC: 0 AN: 80402

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40970

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5546

European-Non Finnish (NFE) AF: 9.22e-7 AC: 1 AN: 1084256

Other (OTH) AF: 0.00 AC: 0 AN: 57640

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.54
BayesDel_addAF	Benign	-0.0060	T
BayesDel_noAF	Benign	-0.25
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.28	T;T;T
Eigen	Benign	0.13
Eigen_PC	Benign	0.099
FATHMM_MKL	Benign	0.45	N
LIST_S2	Benign	0.65	.;T;T
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.20	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N;N;.
PhyloP100		2.2
PrimateAI	Pathogenic	0.96	D
PROVEAN	Benign	-0.95	N;.;.
REVEL	Benign	0.14
Sift	Uncertain	0.012	D;.;.
Sift4G	Uncertain	0.030	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.33
MutPred		0.18		Gain of catalytic residue at V160 (P = 0.0266);Gain of catalytic residue at V160 (P = 0.0266);.;
MVP		0.19
MPC		1.8
ClinPred		0.74	D
GERP RS		2.2
PromoterAI		-0.0015	Neutral
Varity_R		0.088
gMVP		0.30
Mutation Taster		=97/3	polymorphism

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

Other links and lift over

dbSNP: rs201502372; hg19: chr19-45683032;