rs571269735

Variant names:

• chr19-45179662-C-T
• rs571269735
• NM_212550.5:c.366C>T

Your query was ambiguous. Multiple possible variants found:

• chr19-45179662-C-T
• chr19-45179662-C-A
• chr19-45179662-C-G

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.366C>T​(p.His122His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0216 in 1,467,920 control chromosomes in the GnomAD database, including 411 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.016 (19 hom., cov: 32)
  • Exomes 𝑓: 0.022 (392 hom.)
• Consequence: BLOC1S3 NM_212550.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.160
• 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=-0.47).
• BP6: Variant 19-45179662-C-T is Benign according to our data. Variant chr19-45179662-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 162792.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.16 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0156 (2367/152168) while in subpopulation NFE AF = 0.0237 (1614/67966). AF 95% confidence interval is 0.0228. There are 19 homozygotes in GnomAd4. There are 1136 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 19 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.366C>T	p.His122His	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.366C>T	p.His122His	synonymous	Exon 2 of 2	ENSP00000393840.1	Q6QNY0
	BLOC1S3	ENST00000587722.1	TSL:6	c.366C>T	p.His122His	synonymous	Exon 1 of 1	ENSP00000468281.1	Q6QNY0
	BLOC1S3	ENST00000884249.1		c.366C>T	p.His122His	synonymous	Exon 2 of 3	ENSP00000554308.1

Frequencies

GnomAD3 genomes AF: 0.0156 AC: 2369 AN: 152062 Hom.: 19 Cov.: 32

Gnomad AFR AF: 0.00413

Gnomad AMI AF: 0.0329

Gnomad AMR AF: 0.00708

Gnomad ASJ AF: 0.00923

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00744

Gnomad FIN AF: 0.0329

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.0237

Gnomad OTH AF: 0.0139

GnomAD2 exomes AF: 0.0152 AC: 1179 AN: 77346 AF XY: 0.0155

Gnomad AFR exome AF: 0.00346

Gnomad AMR exome AF: 0.00462

Gnomad ASJ exome AF: 0.00736

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0393

Gnomad NFE exome AF: 0.0235

Gnomad OTH exome AF: 0.0143

GnomAD4 exome AF: 0.0223 AC: 29299 AN: 1315752 Hom.: 392 Cov.: 31 AF XY: 0.0217 AC XY: 14061 AN XY: 647930

African (AFR) AF: 0.00267 AC: 71 AN: 26566

American (AMR) AF: 0.00644 AC: 168 AN: 26082

Ashkenazi Jewish (ASJ) AF: 0.00897 AC: 206 AN: 22978

East Asian (EAS) AF: 0.0000347 AC: 1 AN: 28800

South Asian (SAS) AF: 0.00985 AC: 709 AN: 71964

European-Finnish (FIN) AF: 0.0343 AC: 1127 AN: 32864

Middle Eastern (MID) AF: 0.00880 AC: 38 AN: 4318

European-Non Finnish (NFE) AF: 0.0247 AC: 25882 AN: 1047688

Other (OTH) AF: 0.0201 AC: 1097 AN: 54492

GnomAD4 genome AF: 0.0156 AC: 2367 AN: 152168 Hom.: 19 Cov.: 32 AF XY: 0.0153 AC XY: 1136 AN XY: 74388

African (AFR) AF: 0.00412 AC: 171 AN: 41540

American (AMR) AF: 0.00694 AC: 106 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00923 AC: 32 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00745 AC: 36 AN: 4834

European-Finnish (FIN) AF: 0.0329 AC: 348 AN: 10590

Middle Eastern (MID) AF: 0.00342 AC: 1 AN: 292

European-Non Finnish (NFE) AF: 0.0237 AC: 1614 AN: 67966

Other (OTH) AF: 0.0137 AC: 29 AN: 2112

Alfa AF: 0.00715 Hom.: 0

Bravo AF: 0.0126

Asia WGS AF: 0.00497 AC: 18 AN: 3436

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	10
DANN	Benign	0.96
PhyloP100		0.16
PromoterAI		0.66	Over-expression
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	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: rs571269735; hg19: chr19-45682920; COSMIC: COSV107997131; COSMIC: COSV107997131;