5-78984937-C-T

Variant names:

• chr5-78984937-C-T
• rs1478202079
• NM_000046.5:c.312G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_000046.5(ARSB):​c.312G>A​(p.Gln104Gln) variant causes a splice region, synonymous change. The variant allele was found at a frequency of 0.000000805 in 1,242,778 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 8.0e-7 (0 hom.)
• Consequence: ARSB NM_000046.5 splice_region, synonymous
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.96
• 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: PanelApp Australia, Genomics England PanelApp, Illumina, Labcorp Genetics (formerly Invitae), G2P, ClinGen

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARSB	NM_000046.5	MANE Select	c.312G>A	p.Gln104Gln	splice_region synonymous	Exon 1 of 8	NP_000037.2
	ARSB	NM_198709.3		c.312G>A	p.Gln104Gln	splice_region synonymous	Exon 2 of 8	NP_942002.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARSB	ENST00000264914.10	TSL:1 MANE Select	c.312G>A	p.Gln104Gln	splice_region synonymous	Exon 1 of 8	ENSP00000264914.4
	ARSB	ENST00000396151.7	TSL:1	c.312G>A	p.Gln104Gln	splice_region synonymous	Exon 2 of 8	ENSP00000379455.3
	ARSB	ENST00000565165.2	TSL:1	c.312G>A	p.Gln104Gln	splice_region synonymous	Exon 1 of 5	ENSP00000456339.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 8.05e-7 AC: 1 AN: 1242778 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 609572

African (AFR) AF: 0.00 AC: 0 AN: 26382

American (AMR) AF: 0.00 AC: 0 AN: 22426

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20720

East Asian (EAS) AF: 0.00 AC: 0 AN: 28206

South Asian (SAS) AF: 0.00 AC: 0 AN: 52132

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 35884

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3568

European-Non Finnish (NFE) AF: 9.97e-7 AC: 1 AN: 1003262

Other (OTH) AF: 0.00 AC: 0 AN: 50198

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.19
CADD	Benign	22
DANN	Benign	0.97
PhyloP100		4.0
PromoterAI		-0.38	Neutral

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.99
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs1478202079; hg19: chr5-78280760;