rs1554032129

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_ModeratePP5_Moderate

The NM_000046.5(ARSB):ā€‹c.253T>Cā€‹(p.Tyr85His) variant causes a missense change. The variant allele was found at a frequency of 0.000000722 in 1,384,466 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (ā˜…).

Frequency

Genomes: not found (cov: 33)
Exomes š‘“: 7.2e-7 ( 0 hom. )

Consequence

ARSB
NM_000046.5 missense

Scores

11
5
3

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 5.85
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.859
PP5
Variant 5-78984996-A-G is Pathogenic according to our data. Variant chr5-78984996-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 559750.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
ARSBNM_000046.5 linkuse as main transcriptc.253T>C p.Tyr85His missense_variant 1/8 ENST00000264914.10 NP_000037.2 P15848-1A0A024RAJ9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
ARSBENST00000264914.10 linkuse as main transcriptc.253T>C p.Tyr85His missense_variant 1/81 NM_000046.5 ENSP00000264914.4 P15848-1
ARSBENST00000396151.7 linkuse as main transcriptc.253T>C p.Tyr85His missense_variant 2/81 ENSP00000379455.3 P15848-2
ARSBENST00000565165.2 linkuse as main transcriptc.253T>C p.Tyr85His missense_variant 1/51 ENSP00000456339.2 A0A2U3U034

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
7.22e-7
AC:
1
AN:
1384466
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
688248
show subpopulations
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:
9.29e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Mucopolysaccharidosis type 6 Pathogenic:1
Likely pathogenic, criteria provided, single submittercurationLaboratory of Diagnosis and Therapy of Lysosomal Disorders, University of PadovaJan 01, 2018In vitro functional studies supportive of a damaging effect on the gene product (low to no ARSB activity in homozygotes; PS3); Absent from GnomAD (PM2) -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.59
BayesDel_addAF
Pathogenic
0.60
D
BayesDel_noAF
Pathogenic
0.62
CADD
Pathogenic
28
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.88
D;.;.
Eigen
Uncertain
0.53
Eigen_PC
Uncertain
0.50
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Uncertain
0.95
D;D;D
M_CAP
Pathogenic
0.91
D
MetaRNN
Pathogenic
0.86
D;D;D
MetaSVM
Pathogenic
0.85
D
MutationAssessor
Benign
1.0
L;L;.
PrimateAI
Pathogenic
0.91
D
PROVEAN
Pathogenic
-4.5
D;D;D
REVEL
Pathogenic
0.90
Sift
Pathogenic
0.0
D;T;T
Sift4G
Benign
0.071
T;T;T
Polyphen
1.0
D;.;.
Vest4
0.47
MutPred
0.84
Loss of stability (P = 0.0397);Loss of stability (P = 0.0397);Loss of stability (P = 0.0397);
MVP
0.95
MPC
1.0
ClinPred
1.0
D
GERP RS
4.5
Varity_R
0.94
gMVP
0.95

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1554032129; hg19: chr5-78280819; COSMIC: COSV53722279; COSMIC: COSV53722279; API