5-78985127-GCCCCGGCGC-G

Position:

chr5-78985127-GCCCCGGCGC-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PM4BP6_Very_StrongBS1BS2

The NM_000046.5(ARSB):c.113_121delGCGCCGGGG(p.Gly38_Gly40del) variant causes a disruptive 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 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1B:7

Conservation

PhyloP100: 4.28

Variant links:

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]

ARSB links:

ARSB (HGNC:):

ARSB links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARSB	NM_000046.5 linkuse as main transcript	c.113_121delGCGCCGGGG	p.Gly38_Gly40del	disruptive_inframe_deletion	1/8	ENST00000264914.10	NP_000037.2	P15848-1A0A024RAJ9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
ARSB	ENST00000264914.10 linkuse as main transcript	c.113_121delGCGCCGGGG	p.Gly38_Gly40del	disruptive_inframe_deletion	1/8	1	NM_000046.5	ENSP00000264914.4	P15848-1
ARSB	ENST00000396151.7 linkuse as main transcript	c.113_121delGCGCCGGGG	p.Gly38_Gly40del	disruptive_inframe_deletion	2/8	1		ENSP00000379455.3	P15848-2
ARSB	ENST00000565165.2 linkuse as main transcript	c.113_121delGCGCCGGGG	p.Gly38_Gly40del	disruptive_inframe_deletion	1/5	1		ENSP00000456339.2	A0A2U3U034
ARSB	ENST00000521117.1 linkuse as main transcript	c.113_121delGCGCCGGGG	p.Gly38_Gly40del	disruptive_inframe_deletion	2/2	3		ENSP00000428611.1	E5RHC4

Frequencies

GnomAD3 genomes

AF:

0.000501

AC:

AN:

151812

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.00295

AC XY:

209

AN XY:

70752

show subpopulations

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.:

AF XY:

0.00113

AC XY:

742

AN XY:

654160

show subpopulations

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:

AN:

151920

Hom.:

Cov.:

AF XY:

0.000754

AC XY:

AN XY:

74268

show subpopulations

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.:

Bravo

AF:

0.000102

Asia WGS

AF:

0.00293

AC:

AN:

3428

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Mucopolysaccharidosis type 6

Benign:5

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 18, 2021	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	May 01, 2020	- -
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	Labcorp Genetics (formerly Invitae), Labcorp	Jan 26, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	May 17, 2022	- -

not provided

Uncertain:1Benign:1

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

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

Name

Calibrated prediction

Score

Prediction

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over