chr5-78985092-C-T

Position:

• chr5-78985092-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_000046.5(ARSB):​c.157G>A​(p.Asp53Asn) variant causes a missense 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 (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ARSB NM_000046.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 7.38

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]

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PM1: In a binding_site (size 0) in uniprot entity ARSB_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.99
• PP5: Variant 5-78985092-C-T is Pathogenic according to our data. Variant chr5-78985092-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 559725.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARSB	NM_000046.5	c.157G>A	p.Asp53Asn	missense_variant	1/8	ENST00000264914.10	NP_000037.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARSB	ENST00000264914.10	c.157G>A	p.Asp53Asn	missense_variant	1/8	1	NM_000046.5	ENSP00000264914	P1
ARSB	ENST00000396151.7	c.157G>A	p.Asp53Asn	missense_variant	2/8	1		ENSP00000379455
ARSB	ENST00000565165.2	c.157G>A	p.Asp53Asn	missense_variant	1/5	1		ENSP00000456339
ARSB	ENST00000521117.1			downstream_gene_variant		3		ENSP00000428611

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1376298 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 681984

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Mucopolysaccharidosis type 6 Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	Dec 24, 2022	A heterozygous missense variation in exon 1 of ARSB gene that results in amino acid substitution of Aspargine for Aspartic acid at codon 53 was detected. The observed variant c.157G>A (p.Asp53Asn) has not been reported in the 1000 genomes and gnomAD databases. The in-silico predictions for the variant is disease causing by MutationTaster2, SIFT and PROVEAN. In summary, the variant is pathogenic. -
Likely pathogenic, criteria provided, single submitter	curation	Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova	Jan 01, 2018	In vitro functional studies supportive of a damaging effect on the gene product (low to no ARSB activity in homozygotes; PS3);Located in a well-established functional domain (PM1); Absent from GnomAD (PM2); Multiple lines of computational evidence support a deleterious effect on the gene product (PP3); -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jun 08, 2023	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.27
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.98	D;.;.
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	0.98	D;D;D
M_CAP	Pathogenic	0.99	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	0.98	D
MutationAssessor	Pathogenic	4.7	H;H;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.94	D
PROVEAN	Pathogenic	-4.4	D;D;D
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;.;.
Vest4		0.97
MutPred		0.92		Loss of stability (P = 0.0143);Loss of stability (P = 0.0143);Loss of stability (P = 0.0143);
MVP		0.98
MPC		2.8
ClinPred		1.0	D
GERP RS		4.3
Varity_R		0.99
gMVP		0.99

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: rs1554032217; hg19: chr5-78280915;