19-45179290-C-G

Variant names:

• chr19-45179290-C-G
• rs200767686
• NM_212550.5:c.-7C>G

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The ENST00000433642.3(BLOC1S3):​c.-7C>G variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000616 in 1,575,562 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0031 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00035 (4 hom.)
• Consequence: BLOC1S3 ENST00000433642.3 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.362
• Publications: 0 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 19-45179290-C-G is Benign according to our data. Variant chr19-45179290-C-G is described in ClinVar as Benign. ClinVar VariationId is 329470.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000433642.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BLOC1S3	NM_212550.5	MANE Select	c.-7C>G		5_prime_UTR_premature_start_codon_gain	Exon 2 of 2	NP_997715.1
	BLOC1S3	NM_212550.5	MANE Select	c.-7C>G		splice_region	Exon 2 of 2	NP_997715.1
	BLOC1S3	NM_212550.5	MANE Select	c.-7C>G		5_prime_UTR	Exon 2 of 2	NP_997715.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BLOC1S3	ENST00000433642.3	TSL:2 MANE Select	c.-7C>G		5_prime_UTR_premature_start_codon_gain	Exon 2 of 2	ENSP00000393840.1
	BLOC1S3	ENST00000433642.3	TSL:2 MANE Select	c.-7C>G		splice_region	Exon 2 of 2	ENSP00000393840.1
	BLOC1S3	ENST00000433642.3	TSL:2 MANE Select	c.-7C>G		5_prime_UTR	Exon 2 of 2	ENSP00000393840.1

Frequencies

GnomAD3 genomes AF: 0.00312 AC: 475 AN: 152244 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.0107

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00137

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.000776 AC: 159 AN: 204772 AF XY: 0.000538

Gnomad AFR exome AF: 0.0112

Gnomad AMR exome AF: 0.000854

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000649

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000310

Gnomad OTH exome AF: 0.000197

GnomAD4 exome AF: 0.000349 AC: 497 AN: 1423200 Hom.: 4 Cov.: 30 AF XY: 0.000312 AC XY: 221 AN XY: 707322

African (AFR) AF: 0.0108 AC: 336 AN: 31182

American (AMR) AF: 0.000936 AC: 39 AN: 41680

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25244

East Asian (EAS) AF: 0.00 AC: 0 AN: 37940

South Asian (SAS) AF: 0.0000362 AC: 3 AN: 82874

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37520

Middle Eastern (MID) AF: 0.00158 AC: 9 AN: 5692

European-Non Finnish (NFE) AF: 0.0000508 AC: 56 AN: 1101852

Other (OTH) AF: 0.000912 AC: 54 AN: 59216

GnomAD4 genome AF: 0.00311 AC: 474 AN: 152362 Hom.: 2 Cov.: 32 AF XY: 0.00319 AC XY: 238 AN XY: 74516

African (AFR) AF: 0.0107 AC: 443 AN: 41588

American (AMR) AF: 0.00137 AC: 21 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68030

Other (OTH) AF: 0.00189 AC: 4 AN: 2112

Alfa AF: 0.000180 Hom.: 0

Bravo AF: 0.00359

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	5.1
DANN	Benign	0.73
PhyloP100		-0.36
PromoterAI		0.019	Neutral

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs200767686; hg19: chr19-45682548;