ENST00000587566.5:c.-276-66509T>C

Variant names:

• chr19-45192480-T-C
• rs2159324
• ENST00000587566.5:c.-276-66509T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000587566.5(MARK4):​c.-276-66509T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.367 in 151,956 control chromosomes in the GnomAD database, including 11,262 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.37 (11262 hom., cov: 31)
• Consequence: MARK4 ENST00000587566.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.05
• Publications: 19 publications found

Genes affected

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]

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]

BLOC1S3 Gene-Disease associations (from GenCC):

• Hermansky-Pudlak syndrome 8

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, G2P

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.442 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BLOC1S3	XR_001753683.2	n.1424+4740T>C		intron_variant	Intron 3 of 3
BLOC1S3	XR_007066810.1	n.968+4740T>C		intron_variant	Intron 4 of 4
BLOC1S3	XR_007066811.1	n.1424+4740T>C		intron_variant	Intron 3 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MARK4	ENST00000587566.5	c.-276-66509T>C		intron_variant	Intron 1 of 6	5		ENSP00000465414.1
BLOC1S3	ENST00000591569.1	n.180+4740T>C		intron_variant	Intron 2 of 3	3
BLOC1S3	ENST00000593083.1	n.386+4740T>C		intron_variant	Intron 3 of 4	4

Frequencies

GnomAD3 genomes AF: 0.367 AC: 55662 AN: 151838 Hom.: 11257 Cov.: 31

Gnomad AFR AF: 0.185

Gnomad AMI AF: 0.659

Gnomad AMR AF: 0.445

Gnomad ASJ AF: 0.331

Gnomad EAS AF: 0.332

Gnomad SAS AF: 0.411

Gnomad FIN AF: 0.440

Gnomad MID AF: 0.316

Gnomad NFE AF: 0.446

Gnomad OTH AF: 0.355

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.367 AC: 55698 AN: 151956 Hom.: 11262 Cov.: 31 AF XY: 0.367 AC XY: 27223 AN XY: 74260

African (AFR) AF: 0.185 AC: 7666 AN: 41434

American (AMR) AF: 0.445 AC: 6798 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.331 AC: 1149 AN: 3468

East Asian (EAS) AF: 0.333 AC: 1723 AN: 5170

South Asian (SAS) AF: 0.413 AC: 1986 AN: 4810

European-Finnish (FIN) AF: 0.440 AC: 4640 AN: 10548

Middle Eastern (MID) AF: 0.306 AC: 90 AN: 294

European-Non Finnish (NFE) AF: 0.446 AC: 30296 AN: 67950

Other (OTH) AF: 0.357 AC: 752 AN: 2106

Alfa AF: 0.408 Hom.: 41410

Bravo AF: 0.356

Asia WGS AF: 0.384 AC: 1332 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	1.9
DANN	Benign	0.25
PhyloP100		-2.1

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: rs2159324; hg19: chr19-45695738;