19-45179362-G-A

Variant names:

• chr19-45179362-G-A
• NM_212550.5:c.66G>A

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Moderate BP6_Moderate BP7

The NM_212550.5(BLOC1S3):​c.66G>A​(p.Ala22Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000698 in 1,432,850 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: BLOC1S3 NM_212550.5 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0980
• 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 -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.42).
• BP6: Variant 19-45179362-G-A is Benign according to our data. Variant chr19-45179362-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 2708638.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.098 with no splicing effect.

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.66G>A	p.Ala22Ala	synonymous	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.66G>A	p.Ala22Ala	synonymous	Exon 2 of 2	ENSP00000393840.1	Q6QNY0
	BLOC1S3	ENST00000587722.1	TSL:6	c.66G>A	p.Ala22Ala	synonymous	Exon 1 of 1	ENSP00000468281.1	Q6QNY0
	BLOC1S3	ENST00000884249.1		c.66G>A	p.Ala22Ala	synonymous	Exon 2 of 3	ENSP00000554308.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.98e-7 AC: 1 AN: 1432850 Hom.: 0 Cov.: 30 AF XY: 0.00000140 AC XY: 1 AN XY: 712726

African (AFR) AF: 0.00 AC: 0 AN: 31766

American (AMR) AF: 0.00 AC: 0 AN: 43232

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25662

East Asian (EAS) AF: 0.00 AC: 0 AN: 38252

South Asian (SAS) AF: 0.00 AC: 0 AN: 84040

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38570

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5704

European-Non Finnish (NFE) AF: 9.04e-7 AC: 1 AN: 1106044

Other (OTH) AF: 0.00 AC: 0 AN: 59580

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
CADD	Benign	13
DANN	Benign	0.95
PhyloP100		0.098
PromoterAI		-0.0062	Neutral

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

hg19: chr19-45682620;