5-78780398-T-G

Position:

• chr5-78780398-T-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PM4 PP5_Moderate

The NM_000046.5(ARSB):​c.1601A>C​(p.Ter534Serext*?) variant causes a stop lost change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ARSB NM_000046.5 stop_lost
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 6.53

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 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Stoplost variant in NM_000046.5 Downstream stopcodon found after 127 codons.
• PP5: Variant 5-78780398-T-G is Pathogenic according to our data. Variant chr5-78780398-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 854092.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARSB	NM_000046.5	c.1601A>C	p.Ter534Serext*?	stop_lost	8/8	ENST00000264914.10	NP_000037.2
ARSB	XM_011543390.2	c.1601A>C	p.Ter534Serext*?	stop_lost	9/9		XP_011541692.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARSB	ENST00000264914.10	c.1601A>C	p.Ter534Serext*?	stop_lost	8/8	1	NM_000046.5	ENSP00000264914.4
ARSB	ENST00000521011.1	n.566A>C		non_coding_transcript_exon_variant	3/3	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Mucopolysaccharidosis type 6 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 07, 2020

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant results in an extension of the ARSB protein. Other variant(s) that result in a similarly extended protein product (p.*534Glnext*50 and p.*534Trpext*50, also known as p.*534W) have been observed in individuals with ARSB-related conditions (PMID: 8144552, 26909334, 30524696). This suggests that these extensions may be clinically significant. This variant has not been reported in the literature in individuals with ARSB-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change results in a frameshift in the ARSB gene (p.*534Serext*50). While this is not anticipated to result in nonsense mediated decay, it is expected to replace the original stop signal with a serine residue and extend the ARSB protein by an additional 49 amino acids. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.032	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	18
DANN	Benign	0.86
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Uncertain	0.93	D
Vest4		0.084
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

Publications

LitVar

Other links and lift over

dbSNP: rs1554069655; hg19: chr5-78076221;