chr5-78885599-A-T

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM2PP2PP3_StrongPP5_Moderate

The NM_000046.5(ARSB):​c.1127T>A​(p.Val376Glu) 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V376M) has been classified as Benign.

Frequency

Genomes: not found (cov: 32)

Consequence

ARSB
NM_000046.5 missense

Scores

10
7
2

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 9.27

Publications

1 publications found
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]
ARSB Gene-Disease associations (from GenCC):
  • mucopolysaccharidosis type 6
    Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Genomics England PanelApp, Illumina, Labcorp Genetics (formerly Invitae), G2P, ClinGen

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 85 curated pathogenic missense variants (we use a threshold of 10). The gene has 14 curated benign missense variants. Gene score misZ: 0.63089 (below the threshold of 3.09). Trascript score misZ: -0.06109 (below the threshold of 3.09). GenCC associations: The gene is linked to mucopolysaccharidosis type 6.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.951
PP5
Variant 5-78885599-A-T is Pathogenic according to our data. Variant chr5-78885599-A-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 559675.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ARSBNM_000046.5 linkc.1127T>A p.Val376Glu missense_variant Exon 5 of 8 ENST00000264914.10 NP_000037.2 P15848-1A0A024RAJ9

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ARSBENST00000264914.10 linkc.1127T>A p.Val376Glu missense_variant Exon 5 of 8 1 NM_000046.5 ENSP00000264914.4 P15848-1
ARSBENST00000396151.7 linkc.1127T>A p.Val376Glu missense_variant Exon 6 of 8 1 ENSP00000379455.3 P15848-2
ARSBENST00000565165.2 linkc.1127T>A p.Val376Glu missense_variant Exon 5 of 5 1 ENSP00000456339.2 A0A2U3U034
ARSBENST00000521800.2 linkn.309T>A non_coding_transcript_exon_variant Exon 2 of 3 2

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
30
GnomAD4 genome
Cov.:
32

ClinVar

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

Submissions by phenotype

Mucopolysaccharidosis type 6 Pathogenic:1
Jan 01, 2018
Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova
Significance:Likely pathogenic
Review Status:criteria provided, single submitter
Collection Method:curation

In vitro functional studies supportive of a damaging effect on the gene product (low to no ARSB activity in homozygotes; PS3); Absent from GnomAD (PM2); Multiple lines of computational evidence support a deleterious effect on the gene product (PP3) -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.63
BayesDel_addAF
Pathogenic
0.52
D
BayesDel_noAF
Pathogenic
0.51
CADD
Pathogenic
27
DANN
Uncertain
0.99
DEOGEN2
Pathogenic
0.85
D;.;.
Eigen
Uncertain
0.62
Eigen_PC
Uncertain
0.63
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.93
D;D;D
M_CAP
Pathogenic
0.44
D
MetaRNN
Pathogenic
0.95
D;D;D
MetaSVM
Pathogenic
0.99
D
MutationAssessor
Pathogenic
3.6
H;H;.
PhyloP100
9.3
PrimateAI
Benign
0.47
T
PROVEAN
Uncertain
-3.5
D;D;D
REVEL
Pathogenic
0.94
Sift
Uncertain
0.010
D;D;D
Sift4G
Uncertain
0.039
D;T;T
Polyphen
0.59
P;.;.
Vest4
0.95
MVP
1.0
MPC
0.94
ClinPred
0.98
D
GERP RS
5.5
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.81
gMVP
0.95
Mutation Taster
=8/92
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

Publications

Other links and lift over

dbSNP: rs1554079268; hg19: chr5-78181422; API