5-78984960-G-T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Moderate

The NM_000046.5(ARSB):c.289C>A(p.Gln97Lys) 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 Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q97R) has been classified 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

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 9.46

Publications

0 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

ARSB links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 13 ACMG points.

PM1

In a hotspot region, there are 13 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 15 uncertain in NM_000046.5

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr5-78984959-T-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 266120.Status of the report is no_assertion_criteria_provided, 0 stars.

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, 0.943

PP5

Variant 5-78984960-G-T is Pathogenic according to our data. Variant chr5-78984960-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 1710132.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARSB	NM_000046.5 link	c.289C>A	p.Gln97Lys	missense_variant	Exon 1 of 8	ENST00000264914.10	NP_000037.2	P15848-1A0A024RAJ9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ARSB	ENST00000264914.10 link	c.289C>A	p.Gln97Lys	missense_variant	Exon 1 of 8	1	NM_000046.5	ENSP00000264914.4	P15848-1
ARSB	ENST00000396151.7 link	c.289C>A	p.Gln97Lys	missense_variant	Exon 2 of 8	1		ENSP00000379455.3	P15848-2
ARSB	ENST00000565165.2 link	c.289C>A	p.Gln97Lys	missense_variant	Exon 1 of 5	1		ENSP00000456339.2	A0A2U3U034
ARSB	ENST00000521117.1 link	c.*152C>A		downstream_gene_variant		3		ENSP00000428611.1	E5RHC4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

1326384

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

656826

African (AFR)

AF:

0.00

AC:

AN:

27918

American (AMR)

AF:

0.00

AC:

AN:

31048

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22852

East Asian (EAS)

AF:

0.00

AC:

AN:

30236

South Asian (SAS)

AF:

0.00

AC:

AN:

68498

European-Finnish (FIN)

AF:

0.00

AC:

AN:

42262

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4006

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1045794

Other (OTH)

AF:

0.00

AC:

AN:

53770

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Mucopolysaccharidosis type 6

Pathogenic:1

Jul 30, 2022

Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

A homozygous missense variation in exon 1 of the ARSB gene that results in the amino acid substitution of Lysine for Glutamine at codon 97 was detected. The observed variant c.289C>A (p.Gln98Lys) has not been reported in the 1000 genomes and gnomAD databases. Alternative variant chr5:78280782 T⇒C (Gln97Arg) is classified Likely Pathogenic, 0 stars, by ClinVar (and confirmed using ACMG). The variant is present in UniProt protein ARSB_HUMAN metal ion binding domain. The in silico prediction of the variant are possibly damaging by Mutation Taster, LRT, MutPred, FATHMM-MKL, MVP and SIFT. The reference codon is conserved across species. Therefore, the variant meets our criteria to be classified as pathogenic based on absence from controls and in silico prediction models. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.89

BayesDel_addAF

Pathogenic

0.53

BayesDel_noAF

Pathogenic

0.53

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.93

D;.;.

Eigen

Pathogenic

0.81

Eigen_PC

Pathogenic

0.74

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.98

D;D;D

M_CAP

Pathogenic

0.96

MetaRNN

Pathogenic

0.94

D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.2

M;M;.

PhyloP100

9.5

PrimateAI

Pathogenic

0.89

PROVEAN

Uncertain

-3.6

D;D;D

REVEL

Pathogenic

0.89

Sift

Uncertain

0.0090

D;T;T

Sift4G

Benign

0.17

T;T;T

Polyphen

1.0

D;.;.

Vest4

0.63

MutPred

0.80

Gain of MoRF binding (P = 0.0575);Gain of MoRF binding (P = 0.0575);Gain of MoRF binding (P = 0.0575);

MVP

0.99

MPC

0.98

ClinPred

0.99

GERP RS

4.6

PromoterAI

0.087

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.98

gMVP

0.98

Mutation Taster

=39/61

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over