19-45179427-C-G

Variant names:

• chr19-45179427-C-G
• rs281865115
• NM_212550.5:c.131C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_212550.5(BLOC1S3):​c.131C>G​(p.Ser44Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000724 in 1,381,728 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: BLOC1S3 NM_212550.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.961
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17135349).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_212550.5. 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
	BLOC1S3	NM_212550.5	MANE Select	c.131C>G	p.Ser44Trp	missense	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.131C>G	p.Ser44Trp	missense	Exon 2 of 2	ENSP00000393840.1
	BLOC1S3	ENST00000587722.1	TSL:6	c.131C>G	p.Ser44Trp	missense	Exon 1 of 1	ENSP00000468281.1
	MARK4	ENST00000587566.5	TSL:5	c.-276-79562C>G		intron	N/A	ENSP00000465414.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.24e-7 AC: 1 AN: 1381728 Hom.: 0 Cov.: 30 AF XY: 0.00000147 AC XY: 1 AN XY: 682486

African (AFR) AF: 0.00 AC: 0 AN: 29970

American (AMR) AF: 0.00 AC: 0 AN: 35802

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24308

East Asian (EAS) AF: 0.00 AC: 0 AN: 35568

South Asian (SAS) AF: 0.00 AC: 0 AN: 79022

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34974

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5402

European-Non Finnish (NFE) AF: 9.27e-7 AC: 1 AN: 1079262

Other (OTH) AF: 0.00 AC: 0 AN: 57420

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	22
DANN	Benign	0.96
DEOGEN2	Uncertain	0.62	D
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.58
FATHMM_MKL	Benign	0.40	N
LIST_S2	Benign	0.68	T
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.69	N
PhyloP100		0.96
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-2.8	D
REVEL	Benign	0.046
Sift	Uncertain	0.021	D
Sift4G	Benign	0.069	T
Polyphen		0.0060	B
Vest4		0.23
MutPred		0.17		Loss of glycosylation at S44 (P = 0.0091)
MVP		0.29
MPC		2.2
ClinPred		0.54	D
GERP RS		1.9
PromoterAI		-0.0068	Neutral
Varity_R		0.14
gMVP		0.16
Mutation Taster		=85/15	polymorphism

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: rs281865115; hg19: chr19-45682685; COSMIC: COSV104997774; COSMIC: COSV104997774;