rs550086186

Variant names:

• chr5-78985127-GCCCCGGCGC-G
• rs550086186
• NM_000046.5:c.113_121delGCGCCGGGG

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 2P and 16B. PM4 BP6_Very_Strong BS1 BS2

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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:7
• Conservation: PhyloP100: 4.28
• Publications: 2 publications found

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 Gene-Disease associations (from GenCC):

• mucopolysaccharidosis type 6

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen, Illumina, G2P

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 495378.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000046.5. 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
	ARSB	NM_000046.5	MANE Select	c.113_121delGCGCCGGGG	p.Gly38_Gly40del	disruptive_inframe_deletion	Exon 1 of 8	NP_000037.2
	ARSB	NM_198709.3		c.113_121delGCGCCGGGG	p.Gly38_Gly40del	disruptive_inframe_deletion	Exon 2 of 8	NP_942002.1	P15848-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARSB	ENST00000264914.10	TSL:1 MANE Select	c.113_121delGCGCCGGGG	p.Gly38_Gly40del	disruptive_inframe_deletion	Exon 1 of 8	ENSP00000264914.4	P15848-1
	ARSB	ENST00000396151.7	TSL:1	c.113_121delGCGCCGGGG	p.Gly38_Gly40del	disruptive_inframe_deletion	Exon 2 of 8	ENSP00000379455.3	P15848-2
	ARSB	ENST00000565165.2	TSL:1	c.113_121delGCGCCGGGG	p.Gly38_Gly40del	disruptive_inframe_deletion	Exon 1 of 5	ENSP00000456339.2	A0A2U3U034

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

GnomAD2 exomes AF: 0.00213 AC: 262 AN: 123220 AF XY: 0.00295

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 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

African (AFR) AF: 0.00 AC: 0 AN: 27290

American (AMR) AF: 0.00 AC: 0 AN: 28016

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22442

East Asian (EAS) AF: 0.0000329 AC: 1 AN: 30382

South Asian (SAS) AF: 0.0124 AC: 871 AN: 70116

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 44272

Middle Eastern (MID) AF: 0.00364 AC: 17 AN: 4674

European-Non Finnish (NFE) AF: 0.0000679 AC: 71 AN: 1045256

Other (OTH) AF: 0.000908 AC: 49 AN: 53966

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

African (AFR) AF: 0.0000241 AC: 1 AN: 41514

American (AMR) AF: 0.0000655 AC: 1 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5160

South Asian (SAS) AF: 0.0139 AC: 67 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10480

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.0000589 AC: 4 AN: 67884

Other (OTH) AF: 0.000948 AC: 2 AN: 2110

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.000102

Asia WGS AF: 0.00293 AC: 10 AN: 3428

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	Mucopolysaccharidosis type 6 (5)
-	1	1	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		4.3
Mutation Taster		=165/35	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs550086186; hg19: chr5-78280950;