rs1271212818
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PP3_StrongPP5
The NM_000046.5(ARSB):c.236G>A(p.Gly79Glu) variant causes a missense change. The variant allele was found at a frequency of 0.0000013 in 1,539,052 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 Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 7.2e-7 ( 0 hom. )
Consequence
ARSB
NM_000046.5 missense
NM_000046.5 missense
Scores
15
3
1
Clinical Significance
Conservation
PhyloP100: 5.76
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 9 ACMG points.
PM1
?
In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_000046.5
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.985
PP5
?
Variant 5-78985013-C-T is Pathogenic according to our data. Variant chr5-78985013-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 559743.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ARSB | NM_000046.5 | c.236G>A | p.Gly79Glu | missense_variant | 1/8 | ENST00000264914.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ARSB | ENST00000264914.10 | c.236G>A | p.Gly79Glu | missense_variant | 1/8 | 1 | NM_000046.5 | P1 | |
ARSB | ENST00000396151.7 | c.236G>A | p.Gly79Glu | missense_variant | 2/8 | 1 | |||
ARSB | ENST00000565165.2 | c.236G>A | p.Gly79Glu | missense_variant | 1/5 | 1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000658 AC: 1AN: 151934Hom.: 0 Cov.: 33
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GnomAD4 exome AF: 7.21e-7 AC: 1AN: 1387118Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 689592
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GnomAD4 genome ? AF: 0.00000658 AC: 1AN: 151934Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74214
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Mucopolysaccharidosis type 6 Pathogenic:1Uncertain:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jan 16, 2024 | - - |
Uncertain significance, criteria provided, single submitter | curation | Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova | Jan 01, 2018 | Absent from GnomAD (PM2) - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Pathogenic
D;.;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
H;H;.
MutationTaster
Benign
D;D;D
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D;D;D
REVEL
Pathogenic
Sift
Uncertain
D;D;D
Sift4G
Pathogenic
D;D;D
Polyphen
D;.;.
Vest4
MutPred
Gain of sheet (P = 0.0344);Gain of sheet (P = 0.0344);Gain of sheet (P = 0.0344);
MVP
MPC
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at