chr19-45179635-G-A

Variant names:

• chr19-45179635-G-A
• rs546645333
• NM_212550.5:c.339G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_212550.5(BLOC1S3):​c.339G>A​(p.Leu113Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00884 in 1,472,916 control chromosomes in the GnomAD database, including 75 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0070 (6 hom., cov: 32)
  • Exomes 𝑓: 0.0091 (69 hom.)
• Consequence: BLOC1S3 NM_212550.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 2.63
• Publications: 3 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.64).
• BP6: Variant 19-45179635-G-A is Benign according to our data. Variant chr19-45179635-G-A is described in ClinVar as Benign. ClinVar VariationId is 226464.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.63 with no splicing effect.
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.00905 (11956/1320688) while in subpopulation MID AF = 0.0267 (114/4274). AF 95% confidence interval is 0.0227. There are 69 homozygotes in GnomAdExome4. There are 5865 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BLOC1S3	NM_212550.5	MANE Select	c.339G>A	p.Leu113Leu	synonymous	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.339G>A	p.Leu113Leu	synonymous	Exon 2 of 2	ENSP00000393840.1
	BLOC1S3	ENST00000587722.1	TSL:6	c.339G>A	p.Leu113Leu	synonymous	Exon 1 of 1	ENSP00000468281.1
	BLOC1S3	ENST00000884249.1		c.339G>A	p.Leu113Leu	synonymous	Exon 2 of 3	ENSP00000554308.1

Frequencies

GnomAD3 genomes AF: 0.00699 AC: 1063 AN: 152120 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.00200

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00989

Gnomad ASJ AF: 0.0130

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00248

Gnomad FIN AF: 0.00614

Gnomad MID AF: 0.0159

Gnomad NFE AF: 0.0100

Gnomad OTH AF: 0.00909

GnomAD2 exomes AF: 0.00901 AC: 720 AN: 79878 AF XY: 0.00805

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0105

Gnomad ASJ exome AF: 0.0126

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00480

Gnomad NFE exome AF: 0.0114

Gnomad OTH exome AF: 0.0180

GnomAD4 exome AF: 0.00905 AC: 11956 AN: 1320688 Hom.: 69 Cov.: 31 AF XY: 0.00902 AC XY: 5865 AN XY: 650508

African (AFR) AF: 0.00176 AC: 47 AN: 26692

American (AMR) AF: 0.0110 AC: 292 AN: 26656

Ashkenazi Jewish (ASJ) AF: 0.0123 AC: 286 AN: 23182

East Asian (EAS) AF: 0.0000343 AC: 1 AN: 29136

South Asian (SAS) AF: 0.00443 AC: 322 AN: 72672

European-Finnish (FIN) AF: 0.00510 AC: 168 AN: 32950

Middle Eastern (MID) AF: 0.0267 AC: 114 AN: 4274

European-Non Finnish (NFE) AF: 0.00972 AC: 10212 AN: 1050388

Other (OTH) AF: 0.00939 AC: 514 AN: 54738

GnomAD4 genome AF: 0.00699 AC: 1064 AN: 152228 Hom.: 6 Cov.: 32 AF XY: 0.00677 AC XY: 504 AN XY: 74442

African (AFR) AF: 0.00200 AC: 83 AN: 41564

American (AMR) AF: 0.00988 AC: 151 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0130 AC: 45 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00269 AC: 13 AN: 4834

European-Finnish (FIN) AF: 0.00614 AC: 65 AN: 10594

Middle Eastern (MID) AF: 0.0171 AC: 5 AN: 292

European-Non Finnish (NFE) AF: 0.0100 AC: 682 AN: 67976

Other (OTH) AF: 0.00900 AC: 19 AN: 2112

Alfa AF: 0.00773 Hom.: 3

Bravo AF: 0.00743

Asia WGS AF: 0.000877 AC: 3 AN: 3436

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
CADD	Benign	7.1
DANN	Benign	0.96
PhyloP100		2.6
PromoterAI		-0.14	Neutral
Mutation Taster		=99/1	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: rs546645333; hg19: chr19-45682893; COSMIC: COSV50065551; COSMIC: COSV50065551;