rs182286598

Variant names:

• chr19-45179440-C-A
• rs182286598
• NM_212550.5:c.144C>A

Your query was ambiguous. Multiple possible variants found:

• chr19-45179440-C-A
• chr19-45179440-C-T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_212550.5(BLOC1S3):​c.144C>A​(p.Arg48Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0156 in 1,525,754 control chromosomes in the GnomAD database, including 232 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. R48R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.010 (16 hom., cov: 32)
  • Exomes 𝑓: 0.016 (216 hom.)
• Consequence: BLOC1S3 NM_212550.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.333
• Publications: 2 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: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.3).
• BP6: Variant 19-45179440-C-A is Benign according to our data. Variant chr19-45179440-C-A is described in ClinVar as Benign. ClinVar VariationId is 226463.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.333 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0103 (1572/152300) while in subpopulation NFE AF = 0.0177 (1205/68006). AF 95% confidence interval is 0.0169. There are 16 homozygotes in GnomAd4. There are 718 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 16 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_212550.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BLOC1S3	NM_212550.5	MANE Select	c.144C>A	p.Arg48Arg	synonymous	Exon 2 of 2	NP_997715.1	Q6QNY0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BLOC1S3	ENST00000433642.3	TSL:2 MANE Select	c.144C>A	p.Arg48Arg	synonymous	Exon 2 of 2	ENSP00000393840.1	Q6QNY0
	BLOC1S3	ENST00000587722.1	TSL:6	c.144C>A	p.Arg48Arg	synonymous	Exon 1 of 1	ENSP00000468281.1	Q6QNY0
	BLOC1S3	ENST00000884249.1		c.144C>A	p.Arg48Arg	synonymous	Exon 2 of 3	ENSP00000554308.1

Frequencies

GnomAD3 genomes AF: 0.0103 AC: 1572 AN: 152188 Hom.: 16 Cov.: 32

Gnomad AFR AF: 0.00311

Gnomad AMI AF: 0.00877

Gnomad AMR AF: 0.00504

Gnomad ASJ AF: 0.00662

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00890

Gnomad FIN AF: 0.00659

Gnomad MID AF: 0.00637

Gnomad NFE AF: 0.0177

Gnomad OTH AF: 0.00718

GnomAD2 exomes AF: 0.0111 AC: 1445 AN: 129900 AF XY: 0.0109

Gnomad AFR exome AF: 0.00333

Gnomad AMR exome AF: 0.00390

Gnomad ASJ exome AF: 0.00499

Gnomad EAS exome AF: 0.000200

Gnomad FIN exome AF: 0.00922

Gnomad NFE exome AF: 0.0190

Gnomad OTH exome AF: 0.00931

GnomAD4 exome AF: 0.0162 AC: 22245 AN: 1373454 Hom.: 216 Cov.: 30 AF XY: 0.0160 AC XY: 10839 AN XY: 677560

African (AFR) AF: 0.00227 AC: 68 AN: 29964

American (AMR) AF: 0.00401 AC: 138 AN: 34430

Ashkenazi Jewish (ASJ) AF: 0.00558 AC: 135 AN: 24194

East Asian (EAS) AF: 0.000114 AC: 4 AN: 35204

South Asian (SAS) AF: 0.00967 AC: 758 AN: 78380

European-Finnish (FIN) AF: 0.0104 AC: 357 AN: 34226

Middle Eastern (MID) AF: 0.00401 AC: 21 AN: 5242

European-Non Finnish (NFE) AF: 0.0186 AC: 19939 AN: 1074664

Other (OTH) AF: 0.0144 AC: 825 AN: 57150

GnomAD4 genome AF: 0.0103 AC: 1572 AN: 152300 Hom.: 16 Cov.: 32 AF XY: 0.00964 AC XY: 718 AN XY: 74476

African (AFR) AF: 0.00310 AC: 129 AN: 41570

American (AMR) AF: 0.00503 AC: 77 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00662 AC: 23 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00891 AC: 43 AN: 4828

European-Finnish (FIN) AF: 0.00659 AC: 70 AN: 10624

Middle Eastern (MID) AF: 0.00685 AC: 2 AN: 292

European-Non Finnish (NFE) AF: 0.0177 AC: 1205 AN: 68006

Other (OTH) AF: 0.00710 AC: 15 AN: 2112

Alfa AF: 0.0126 Hom.: 2

Bravo AF: 0.00941

Asia WGS AF: 0.00346 AC: 12 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.30
CADD	Benign	12
DANN	Benign	0.93
PhyloP100		-0.33
PromoterAI		0.072	Neutral
Mutation Taster		=100/0	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: rs182286598; hg19: chr19-45682698; COSMIC: COSV50064998; COSMIC: COSV50064998;