chr5-78780402-TCCAAGGGCCCCACAC-T

Variant names:

• chr5-78780402-TCCAAGGGCCCCACAC-T
• rs1554069658
• NM_000046.5:c.1582_1596delGTGTGGGGCCCTTGG

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM4 PP3

The NM_000046.5(ARSB):​c.1582_1596delGTGTGGGGCCCTTGG​(p.Val528_Trp532del) variant causes a conservative inframe deletion change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. V528V) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ARSB NM_000046.5 conservative_inframe_deletion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.42
• Publications: 1 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: PanelApp Australia, Genomics England PanelApp, Illumina, Labcorp Genetics (formerly Invitae), G2P, ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_000046.5.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARSB	NM_000046.5	c.1582_1596delGTGTGGGGCCCTTGG	p.Val528_Trp532del	conservative_inframe_deletion	Exon 8 of 8	ENST00000264914.10	NP_000037.2
ARSB	XM_011543390.2	c.1582_1596delGTGTGGGGCCCTTGG	p.Val528_Trp532del	conservative_inframe_deletion	Exon 9 of 9		XP_011541692.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARSB	ENST00000264914.10	c.1582_1596delGTGTGGGGCCCTTGG	p.Val528_Trp532del	conservative_inframe_deletion	Exon 8 of 8	1	NM_000046.5	ENSP00000264914.4
ARSB	ENST00000521011.1	n.547_561delGTGTGGGGCCCTTGG		non_coding_transcript_exon_variant	Exon 3 of 3	3

Frequencies

GnomAD3 genomes Cov.: 32

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

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Mucopolysaccharidosis type 6 Uncertain:1

Jan 01, 2018

Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

Absent from GnomAD (PM2) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		8.4
Mutation Taster		=16/184	disease causing (long InDel)

Splicing

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

Other links and lift over

dbSNP: rs1554069658; hg19: chr5-78076225;