chr19-45205630-T-C

Variant names:

• chr19-45205630-T-C
• rs597668
• ENST00000587566.5:c.-276-53359T>C

Variant summary

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

The ENST00000587566.5(MARK4):​c.-276-53359T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.266 in 151,972 control chromosomes in the GnomAD database, including 6,417 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 0.27 (6417 hom., cov: 32)
• Consequence: MARK4 ENST00000587566.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.13
• Publications: 48 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=-1.0).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.413 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000587566.5. 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

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MARK4	ENST00000587566.5	TSL:5	c.-276-53359T>C		intron	N/A	ENSP00000465414.1
	BLOC1S3	ENST00000591569.1	TSL:3	n.282+3123T>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.265 AC: 40307 AN: 151854 Hom.: 6393 Cov.: 32

Gnomad AFR AF: 0.418

Gnomad AMI AF: 0.291

Gnomad AMR AF: 0.303

Gnomad ASJ AF: 0.0738

Gnomad EAS AF: 0.364

Gnomad SAS AF: 0.323

Gnomad FIN AF: 0.251

Gnomad MID AF: 0.152

Gnomad NFE AF: 0.166

Gnomad OTH AF: 0.214

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

GnomAD4 genome AF: 0.266 AC: 40388 AN: 151972 Hom.: 6417 Cov.: 32 AF XY: 0.272 AC XY: 20204 AN XY: 74266

African (AFR) AF: 0.418 AC: 17331 AN: 41470

American (AMR) AF: 0.303 AC: 4616 AN: 15232

Ashkenazi Jewish (ASJ) AF: 0.0738 AC: 256 AN: 3470

East Asian (EAS) AF: 0.365 AC: 1890 AN: 5172

South Asian (SAS) AF: 0.323 AC: 1558 AN: 4818

European-Finnish (FIN) AF: 0.251 AC: 2643 AN: 10548

Middle Eastern (MID) AF: 0.153 AC: 45 AN: 294

European-Non Finnish (NFE) AF: 0.167 AC: 11315 AN: 67944

Other (OTH) AF: 0.222 AC: 469 AN: 2112

Alfa AF: 0.176 Hom.: 1504

Bravo AF: 0.275

Asia WGS AF: 0.433 AC: 1504 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	1.8
DANN	Benign	0.56
PhyloP100		-1.1

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs597668; hg19: chr19-45708888;