Genetic Variant MARK4:c.-276-53359T>C (chr19-45205630-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

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

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.13

Publications

48 publications found

Variant links:

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]

MARK4 links:

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

BLOC1S3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank
BLOC1S3	XR_007066811.1 link	n.1526+3123T>C	intron_variant	Intron 4 of 4
BLOC1S3	XR_007066812.1 link	n.1526+3123T>C	intron_variant	Intron 4 of 4
BLOC1S3	XR_007066813.1 link	n.1498+3123T>C	intron_variant	Intron 4 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MARK4	ENST00000587566.5 link	c.-276-53359T>C		intron_variant	Intron 1 of 6	5		ENSP00000465414.1
BLOC1S3	ENST00000591569.1 link	n.282+3123T>C		intron_variant	Intron 3 of 3	3

Frequencies

GnomAD3 genomes

AF:

0.265

AC:

40307

AN:

151854

Hom.:

6393

Cov.:

show subpopulations

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.:

AF XY:

0.272

AC XY:

20204

AN XY:

74266

show subpopulations

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:

AN:

294

European-Non Finnish (NFE)

AF:

0.167

AC:

11315

AN:

67944

Other (OTH)

AF:

0.222

AC:

469

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1413

2827

4240

5654

7067

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

408

816

1224

1632

2040

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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 v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-1.0

CADD

Benign

1.8

(source)

DANN

Benign

0.56

PhyloP100

-1.1

Splicing

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over