5-78777851-CAAAAAAAAA-CAAAAAAAAAAAA

Variant names:

• chr5-78777851-C-CAAA
• rs397976147
• NM_000046.5:c.*2543_*2545dupTTT

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BS1_Supporting BS2

The NM_000046.5(ARSB):​c.*2543_*2545dupTTT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.016 (24 hom., cov: 0)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ARSB NM_000046.5 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.633
• 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: Likely_benign. The variant received -5 ACMG points.

• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0159 (1360/85362) while in subpopulation AFR AF = 0.0301 (636/21156). AF 95% confidence interval is 0.0281. There are 24 homozygotes in GnomAd4. There are 594 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 24 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARSB	NM_000046.5	c.*2543_*2545dupTTT		3_prime_UTR_variant	Exon 8 of 8	ENST00000264914.10	NP_000037.2
ARSB	XM_011543390.2	c.*2543_*2545dupTTT		3_prime_UTR_variant	Exon 9 of 9		XP_011541692.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARSB	ENST00000264914.10	c.*2543_*2545dupTTT		3_prime_UTR_variant	Exon 8 of 8	1	NM_000046.5	ENSP00000264914.4

Frequencies

GnomAD3 genomes AF: 0.0159 AC: 1360 AN: 85384 Hom.: 24 Cov.: 0

Gnomad AFR AF: 0.0301

Gnomad AMI AF: 0.0487

Gnomad AMR AF: 0.0114

Gnomad ASJ AF: 0.0418

Gnomad EAS AF: 0.00514

Gnomad SAS AF: 0.00261

Gnomad FIN AF: 0.00360

Gnomad MID AF: 0.00562

Gnomad NFE AF: 0.0104

Gnomad OTH AF: 0.0112

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 2 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 2

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 2

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.0159 AC: 1360 AN: 85362 Hom.: 24 Cov.: 0 AF XY: 0.0151 AC XY: 594 AN XY: 39298

African (AFR) AF: 0.0301 AC: 636 AN: 21156

American (AMR) AF: 0.0114 AC: 77 AN: 6768

Ashkenazi Jewish (ASJ) AF: 0.0418 AC: 104 AN: 2490

East Asian (EAS) AF: 0.00515 AC: 17 AN: 3300

South Asian (SAS) AF: 0.00219 AC: 5 AN: 2286

European-Finnish (FIN) AF: 0.00360 AC: 10 AN: 2780

Middle Eastern (MID) AF: 0.00617 AC: 1 AN: 162

European-Non Finnish (NFE) AF: 0.0104 AC: 465 AN: 44662

Other (OTH) AF: 0.0111 AC: 12 AN: 1080

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Mucopolysaccharidosis type 6 Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.63
Mutation Taster		=100/0	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs397976147; hg19: chr5-78073674;