rs1554032222

Variant names:

• chr5-78985100-A-T
• rs1554032222
• NM_000046.5:c.149T>A

Your query was ambiguous. Multiple possible variants found:

• chr5-78985100-A-T
• chr5-78985100-A-C
• chr5-78985100-A-G

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_000046.5(ARSB):​c.149T>A​(p.Leu50*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. L50L) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ARSB NM_000046.5 stop_gained
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 8.69
• 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: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen, Illumina, G2P

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-78985100-A-T is Pathogenic according to our data. Variant chr5-78985100-A-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 559718.Status of the report is criteria_provided_single_submitter, 1 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.149T>A	p.Leu50*	stop_gained	Exon 1 of 8	NP_000037.2
	ARSB	NM_198709.3		c.149T>A	p.Leu50*	stop_gained	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.149T>A	p.Leu50*	stop_gained	Exon 1 of 8	ENSP00000264914.4	P15848-1
	ARSB	ENST00000396151.7	TSL:1	c.149T>A	p.Leu50*	stop_gained	Exon 2 of 8	ENSP00000379455.3	P15848-2
	ARSB	ENST00000565165.2	TSL:1	c.149T>A	p.Leu50*	stop_gained	Exon 1 of 5	ENSP00000456339.2	A0A2U3U034

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Mucopolysaccharidosis type 6 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.68	D
BayesDel_noAF	Pathogenic	0.65
CADD	Pathogenic	43
DANN	Uncertain	0.98
Eigen	Pathogenic	0.96
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Uncertain	0.96	D
PhyloP100		8.7
Vest4		0.57
GERP RS		4.3
PromoterAI		-0.046	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=1/199	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs1554032222; hg19: chr5-78280923;