5-78984965-C-G

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2PM5PP3_Strong

The NM_000046.5(ARSB):ā€‹c.284G>Cā€‹(p.Arg95Pro) variant causes a missense change. The variant allele was found at a frequency of 0.0000015 in 1,336,738 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R95Q) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 33)
Exomes š‘“: 0.0000015 ( 0 hom. )

Consequence

ARSB
NM_000046.5 missense

Scores

15
3
1

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.73
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 8 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr5-78984965-C-T is described in Lovd as [Likely_pathogenic].
PP3
MetaRNN computational evidence supports a deleterious effect, 0.982

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
ARSBNM_000046.5 linkc.284G>C p.Arg95Pro 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 linkc.284G>C p.Arg95Pro missense_variant 1/81 NM_000046.5 ENSP00000264914.4 P15848-1
ARSBENST00000396151.7 linkc.284G>C p.Arg95Pro missense_variant 2/81 ENSP00000379455.3 P15848-2
ARSBENST00000565165.2 linkc.284G>C p.Arg95Pro missense_variant 1/51 ENSP00000456339.2 A0A2U3U034

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD3 exomes
AF:
0.00000678
AC:
1
AN:
147456
Hom.:
0
AF XY:
0.0000119
AC XY:
1
AN XY:
84196
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000149
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000150
AC:
2
AN:
1336738
Hom.:
0
Cov.:
31
AF XY:
0.00000302
AC XY:
2
AN XY:
662560
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:
0.0000142
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
9.51e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.99
BayesDel_addAF
Pathogenic
0.65
D
BayesDel_noAF
Pathogenic
0.70
CADD
Pathogenic
33
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.99
D;.;.
Eigen
Pathogenic
0.92
Eigen_PC
Pathogenic
0.79
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Pathogenic
0.99
D;D;D
M_CAP
Pathogenic
0.99
D
MetaRNN
Pathogenic
0.98
D;D;D
MetaSVM
Pathogenic
1.0
D
MutationAssessor
Pathogenic
5.0
H;H;.
PrimateAI
Pathogenic
0.86
D
PROVEAN
Pathogenic
-6.0
D;D;D
REVEL
Pathogenic
0.98
Sift
Uncertain
0.0010
D;D;D
Sift4G
Uncertain
0.0020
D;D;D
Polyphen
1.0
D;.;.
Vest4
0.90
MutPred
0.87
Gain of glycosylation at R95 (P = 0.0082);Gain of glycosylation at R95 (P = 0.0082);Gain of glycosylation at R95 (P = 0.0082);
MVP
1.0
MPC
1.0
ClinPred
1.0
D
GERP RS
4.6
Varity_R
1.0
gMVP
1.0

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: rs118203942; hg19: chr5-78280788; API