rs75792246

Variant names:

• chr19-45179618-C-G
• rs75792246
• NM_212550.5:c.322C>G

Your query was ambiguous. Multiple possible variants found:

• chr19-45179618-C-G
• chr19-45179618-C-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_212550.5(BLOC1S3):​c.322C>G​(p.Leu108Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0407 in 1,475,054 control chromosomes in the GnomAD database, including 1,432 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. L108L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.029 (102 hom., cov: 32)
  • Exomes 𝑓: 0.042 (1330 hom.)
• Consequence: BLOC1S3 NM_212550.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 1.20
• Publications: 7 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008262664).
• BP6: Variant 19-45179618-C-G is Benign according to our data. Variant chr19-45179618-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 179946.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0291 (4425/152234) while in subpopulation NFE AF = 0.044 (2988/67978). AF 95% confidence interval is 0.0426. There are 102 homozygotes in GnomAd4. There are 2131 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 102 AR gene

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.322C>G	p.Leu108Val	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.322C>G	p.Leu108Val	missense	Exon 2 of 2	ENSP00000393840.1	Q6QNY0
	BLOC1S3	ENST00000587722.1	TSL:6	c.322C>G	p.Leu108Val	missense	Exon 1 of 1	ENSP00000468281.1	Q6QNY0
	BLOC1S3	ENST00000884249.1		c.322C>G	p.Leu108Val	missense	Exon 2 of 3	ENSP00000554308.1

Frequencies

GnomAD3 genomes AF: 0.0291 AC: 4425 AN: 152126 Hom.: 102 Cov.: 32

Gnomad AFR AF: 0.00719

Gnomad AMI AF: 0.0758

Gnomad AMR AF: 0.0221

Gnomad ASJ AF: 0.0115

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.00827

Gnomad FIN AF: 0.0570

Gnomad MID AF: 0.00321

Gnomad NFE AF: 0.0439

Gnomad OTH AF: 0.0216

GnomAD2 exomes AF: 0.0255 AC: 2078 AN: 81378 AF XY: 0.0251

Gnomad AFR exome AF: 0.00951

Gnomad AMR exome AF: 0.0176

Gnomad ASJ exome AF: 0.0144

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0479

Gnomad NFE exome AF: 0.0414

Gnomad OTH exome AF: 0.0235

GnomAD4 exome AF: 0.0420 AC: 55597 AN: 1322820 Hom.: 1330 Cov.: 31 AF XY: 0.0411 AC XY: 26805 AN XY: 651658

African (AFR) AF: 0.00619 AC: 165 AN: 26644

American (AMR) AF: 0.0182 AC: 489 AN: 26938

Ashkenazi Jewish (ASJ) AF: 0.0142 AC: 329 AN: 23232

East Asian (EAS) AF: 0.0000341 AC: 1 AN: 29352

South Asian (SAS) AF: 0.00936 AC: 681 AN: 72784

European-Finnish (FIN) AF: 0.0472 AC: 1554 AN: 32946

Middle Eastern (MID) AF: 0.00530 AC: 22 AN: 4154

European-Non Finnish (NFE) AF: 0.0478 AC: 50316 AN: 1051910

Other (OTH) AF: 0.0372 AC: 2040 AN: 54860

GnomAD4 genome AF: 0.0291 AC: 4425 AN: 152234 Hom.: 102 Cov.: 32 AF XY: 0.0286 AC XY: 2131 AN XY: 74440

African (AFR) AF: 0.00714 AC: 297 AN: 41568

American (AMR) AF: 0.0220 AC: 337 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0115 AC: 40 AN: 3472

East Asian (EAS) AF: 0.000579 AC: 3 AN: 5182

South Asian (SAS) AF: 0.00849 AC: 41 AN: 4832

European-Finnish (FIN) AF: 0.0570 AC: 604 AN: 10596

Middle Eastern (MID) AF: 0.00345 AC: 1 AN: 290

European-Non Finnish (NFE) AF: 0.0440 AC: 2988 AN: 67978

Other (OTH) AF: 0.0213 AC: 45 AN: 2110

Alfa AF: 0.0334 Hom.: 15

Bravo AF: 0.0259

ExAC AF: 0.00905 AC: 126

Asia WGS AF: 0.00408 AC: 14 AN: 3448

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.77	D
Eigen	Uncertain	0.31
Eigen_PC	Benign	0.21
FATHMM_MKL	Benign	0.51	D
LIST_S2	Benign	0.53	T
MetaRNN	Benign	0.0083	T
MetaSVM	Benign	-0.45	T
MutationAssessor	Benign	1.9	L
PhyloP100		1.2
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-2.2	N
REVEL	Benign	0.11
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.18	T
Polyphen		1.0	D
Vest4		0.31
MPC		2.0
ClinPred		0.029	T
GERP RS		3.7
PromoterAI		-0.038	Neutral
Varity_R		0.53
gMVP		0.31
Mutation Taster		=94/6	polymorphism (auto)

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: rs75792246; hg19: chr19-45682876; COSMIC: COSV99135287; COSMIC: COSV99135287;