19-45179290-C-G

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_212550.5(BLOC1S3):c.-7C>G variant causes a splice region, 5 prime UTR 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. 1/1 splice prediction tools predict no significant impact on normal splicing. 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 NM_212550.5 splice_region, 5_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.362

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 Benign. Variant got -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 id is 329470.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BLOC1S3	NM_212550.5	c.-7C>G		splice_region_variant, 5_prime_UTR_variant	2/2	ENST00000433642.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BLOC1S3	ENST00000433642.3	c.-7C>G		splice_region_variant, 5_prime_UTR_variant	2/2	2	NM_212550.5	P1
BLOC1S3	ENST00000587722.1	c.-7C>G		5_prime_UTR_variant	1/1			P1
MARK4	ENST00000587566.5	c.-276-79699C>G		intron_variant		5

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

GnomAD3 exomes AF: 0.000776 AC: 159 AN: 204772 Hom.: 0 AF XY: 0.000538 AC XY: 61 AN XY: 113374

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 SAS exome AF: 0.000111

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

Gnomad4 AFR exome AF: 0.0108

Gnomad4 AMR exome AF: 0.000936

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000362

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000508

Gnomad4 OTH exome AF: 0.000912

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

Gnomad4 AFR AF: 0.0107

Gnomad4 AMR AF: 0.00137

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.000180 Hom.: 0

Bravo AF: 0.00359

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Aug 18, 2016

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
Cadd	Benign	5.1
Dann	Benign	0.73

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

Publications

LitVar

Other links and lift over

dbSNP: rs200767686; hg19: chr19-45682548;