chr19-45179382-G-A

Variant names:

• chr19-45179382-G-A
• rs370018943
• NM_212550.5:c.86G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_212550.5(BLOC1S3):​c.86G>A​(p.Arg29His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R29L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: BLOC1S3 NM_212550.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0560
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.051520318).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BLOC1S3	NM_212550.5	MANE Select	c.86G>A	p.Arg29His	missense	Exon 2 of 2	NP_997715.1	Q6QNY0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BLOC1S3	ENST00000433642.3	TSL:2 MANE Select	c.86G>A	p.Arg29His	missense	Exon 2 of 2	ENSP00000393840.1	Q6QNY0
	BLOC1S3	ENST00000587722.1	TSL:6	c.86G>A	p.Arg29His	missense	Exon 1 of 1	ENSP00000468281.1	Q6QNY0
	BLOC1S3	ENST00000884249.1		c.86G>A	p.Arg29His	missense	Exon 2 of 3	ENSP00000554308.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1429006 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 710626

African (AFR) AF: 0.00 AC: 0 AN: 31590

American (AMR) AF: 0.00 AC: 0 AN: 42836

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25590

East Asian (EAS) AF: 0.00 AC: 0 AN: 37976

South Asian (SAS) AF: 0.00 AC: 0 AN: 83664

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38378

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5696

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1103892

Other (OTH) AF: 0.00 AC: 0 AN: 59384

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000491

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	14
DANN	Uncertain	0.98
DEOGEN2	Benign	0.16	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.052	N
LIST_S2	Benign	0.49	T
M_CAP	Benign	0.0037	T
MetaRNN	Benign	0.052	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.056
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-0.40	N
REVEL	Benign	0.025
Sift	Benign	0.18	T
Sift4G	Benign	0.19	T
Polyphen		0.030	B
Vest4		0.063
MutPred		0.12		Gain of glycosylation at S30 (P = 0.1026)
MVP		0.095
MPC		1.1
ClinPred		0.083	T
GERP RS		0.24
PromoterAI		0.019	Neutral
Varity_R		0.031
gMVP		0.20
Mutation Taster		=98/2	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: rs370018943; hg19: chr19-45682640;