rs1554032243

Variant names:

• chr5-78985125-TGGCCCCGG-T
• rs1554032243
• NM_000046.5:c.116_123delCCGGGGCC

Variant summary

Our verdict is Pathogenic. The variant received 22 ACMG points: 22P and 0B. PVS1 PS3 PM2 PP5_Very_Strong

The NM_000046.5(ARSB):​c.116_123delCCGGGGCC​(p.Ala39GlufsTer85) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000802962: "In vitro functional studies supportive of a damaging effect on the gene product (low to no ARSB activity in homozygotes" and additional evidence is available in ClinVar. Synonymous variant affecting the same amino acid position (i.e. A39A) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ARSB NM_000046.5 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 4.28
• Publications: 0 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: Pathogenic. The variant received 22 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV000802962: "In vitro functional studies supportive of a damaging effect on the gene product (low to no ARSB activity in homozygotes;"
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-78985125-TGGCCCCGG-T is Pathogenic according to our data. Variant chr5-78985125-TGGCCCCGG-T is described in ClinVar as Pathogenic. ClinVar VariationId is 495377.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.116_123delCCGGGGCC	p.Ala39GlufsTer85	frameshift	Exon 1 of 8	NP_000037.2
	ARSB	NM_198709.3		c.116_123delCCGGGGCC	p.Ala39GlufsTer85	frameshift	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.116_123delCCGGGGCC	p.Ala39GlufsTer85	frameshift	Exon 1 of 8	ENSP00000264914.4	P15848-1
	ARSB	ENST00000396151.7	TSL:1	c.116_123delCCGGGGCC	p.Ala39GlufsTer85	frameshift	Exon 2 of 8	ENSP00000379455.3	P15848-2
	ARSB	ENST00000565165.2	TSL:1	c.116_123delCCGGGGCC	p.Ala39GlufsTer85	frameshift	Exon 1 of 5	ENSP00000456339.2	A0A2U3U034

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	Mucopolysaccharidosis type 6 (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		4.3
Mutation Taster		=4/196	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs1554032243; hg19: chr5-78280948;