rs550086186

chr5-78985127-GCCCCGGCGC-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PM4 BP6_Very_Strong BS1 BS2

The NM_000046.5(ARSB):c.113_121del(p.Gly38_Gly40del) variant causes a inframe deletion change. The variant allele was found at a frequency of 0.000733 in 1,478,334 control chromosomes in the GnomAD database, including 19 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00049 (2 hom., cov: 33)
  • Exomes 𝑓: 0.00076 (17 hom.)
• Consequence: ARSB NM_000046.5 inframe_deletion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:7
• Conservation: PhyloP100: 4.28

Genes affected

ARSB (HGNC:714): (arylsulfatase B) Arylsulfatase B encoded by this gene belongs to the sulfatase family. The arylsulfatase B homodimer hydrolyzes sulfate groups of N-Acetyl-D-galactosamine, chondriotin sulfate, and dermatan sulfate. The protein is targeted to the lysozyme. Mucopolysaccharidosis type VI is an autosomal recessive lysosomal storage disorder resulting from a deficiency of arylsulfatase B. Two alternatively spliced transcript variants encoding distinct isoforms have been found for this gene. [provided by RefSeq, Dec 2016]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_000046.5.
• BP6: Variant 5-78985127-GCCCCGGCGC-G is Benign according to our data. Variant chr5-78985127-GCCCCGGCGC-G is described in ClinVar as [Likely_benign]. Clinvar id is 495378.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-78985127-GCCCCGGCGC-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000494 (75/151920) while in subpopulation SAS AF= 0.0139 (67/4828). AF 95% confidence interval is 0.0112. There are 2 homozygotes in gnomad4. There are 56 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARSB	NM_000046.5	c.113_121del	p.Gly38_Gly40del	inframe_deletion	1/8	ENST00000264914.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARSB	ENST00000264914.10	c.113_121del	p.Gly38_Gly40del	inframe_deletion	1/8	1	NM_000046.5	P1
ARSB	ENST00000396151.7	c.113_121del	p.Gly38_Gly40del	inframe_deletion	2/8	1
ARSB	ENST00000565165.2	c.113_121del	p.Gly38_Gly40del	inframe_deletion	1/5	1
ARSB	ENST00000521117.1	c.113_121del	p.Gly38_Gly40del	inframe_deletion	2/2	3

Frequencies

GnomAD3 genomes AF: 0.000501 AC: 76 AN: 151812 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000656

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0141

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000589

Gnomad OTH AF: 0.000958

GnomAD3 exomes AF: 0.00213 AC: 262 AN: 123220 Hom.: 6 AF XY: 0.00295 AC XY: 209 AN XY: 70752

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0137

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000213

Gnomad OTH exome AF: 0.00109

GnomAD4 exome AF: 0.000761 AC: 1009 AN: 1326414 Hom.: 17 AF XY: 0.00113 AC XY: 742 AN XY: 654160

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000329

Gnomad4 SAS exome AF: 0.0124

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000679

Gnomad4 OTH exome AF: 0.000908

GnomAD4 genome AF: 0.000494 AC: 75 AN: 151920 Hom.: 2 Cov.: 33 AF XY: 0.000754 AC XY: 56 AN XY: 74268

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0139

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000589

Gnomad4 OTH AF: 0.000948

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.000102

Asia WGS AF: 0.00293 AC: 10 AN: 3428

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1 Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Mucopolysaccharidosis type 6 Benign:5

Benign, criteria provided, single submitter	curation	Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova	Jan 01, 2018	In frame deletion in a repetitive region without a known function (BP3); Allele frequency greater than expected for disorder (BS1). Homozygotes reported in ExAC (BS2) -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 26, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 18, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	May 17, 2022	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	May 01, 2020	- -

not provided Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2023	ARSB: BS1, BS2 -
Uncertain significance, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Apr 12, 2017	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jul 18, 2019

Variant summary: ARSB c.113_121delGCGCCGGGG (p.Gly38_Gly40del) results in an in-frame deletion that is predicted to remove three amino acids from the encoded protein. The variant allele was found at a frequency of 0.0021 in 123320 control chromosomes, predominantly at a frequency of 0.014 within the South Asian subpopulation in the gnomAD database, including 6 homozygotes. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 6 fold of the estimated maximal expected allele frequency for a pathogenic variant in ARSB causing Mucopolysaccharidosis Type VI (Maroteaux-Lamy Syndrome) phenotype (0.0022), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. The variant, c.113_121delGCGCCGGGG has been reported in the literature in a homozygous individual affected with Mucopolysaccharidosis Type VI, with an attenuated disease severity (Mathew_2015). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two other submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (1x benign and 1x uncertain significance). Based on the evidence outlined above, the variant was classified as benign. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs550086186; hg19: chr5-78280950;