Genetic Variant ARSB:p.Arg106His (chr5-78969188-C-T) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 5P and 9B. PM1PM5PP2BP4_StrongBP6BS1

The NM_000046.5(ARSB):c.317G>A(p.Arg106His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000465 in 1,613,976 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R106C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0021 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00030 ( 1 hom. )

Consequence

ARSB
NM_000046.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:4

Conservation

PhyloP100: 2.71

Publications

7 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: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen, Illumina, G2P

ARSB links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

PM1

In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_000046.5

PM5

Other missense variant is known to change same aminoacid residue: Variant chr5-78969188-C-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 450885.Status of the report is criteria_provided_single_submitter, 1 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.

BP4

Computational evidence support a benign effect (MetaRNN=0.012774408).

BP6

Variant 5-78969188-C-T is Benign according to our data. Variant chr5-78969188-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 558775.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0021 (319/152210) while in subpopulation AFR AF = 0.00725 (301/41526). AF 95% confidence interval is 0.00657. There are 0 homozygotes in GnomAd4. There are 163 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000046.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARSB	NM_000046.5	MANE Select	c.317G>A	p.Arg106His	missense	Exon 2 of 8	NP_000037.2
	ARSB	NM_198709.3		c.317G>A	p.Arg106His	missense	Exon 3 of 8	NP_942002.1	P15848-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ARSB	ENST00000264914.10	TSL:1 MANE Select	c.317G>A	p.Arg106His	missense	Exon 2 of 8	ENSP00000264914.4	P15848-1
ARSB	ENST00000396151.7	TSL:1	c.317G>A	p.Arg106His	missense	Exon 3 of 8	ENSP00000379455.3	P15848-2
ARSB	ENST00000565165.2	TSL:1	c.317G>A	p.Arg106His	missense	Exon 2 of 5	ENSP00000456339.2	A0A2U3U034

Frequencies

GnomAD3 genomes

AF:

0.00210

AC:

319

AN:

152094

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00727

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000786

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000208

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00143

GnomAD2 exomes

AF:

0.000653

AC:

164

AN:

251190

AF XY:

0.000493

show subpopulations

Gnomad AFR exome

AF:

0.00819

Gnomad AMR exome

AF:

0.000607

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.0000352

Gnomad OTH exome

AF:

0.000653

GnomAD4 exome

AF:

0.000296

AC:

432

AN:

1461766

Hom.:

Cov.:

AF XY:

0.000271

AC XY:

197

AN XY:

727194

show subpopulations

African (AFR)

AF:

0.00875

AC:

293

AN:

33480

American (AMR)

AF:

0.000760

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.0000756

AC:

AN:

39696

South Asian (SAS)

AF:

0.000116

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.000695

AC:

AN:

5752

European-Non Finnish (NFE)

AF:

0.0000342

AC:

AN:

1111914

Other (OTH)

AF:

0.000828

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

111

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00210

AC:

319

AN:

152210

Hom.:

Cov.:

AF XY:

0.00219

AC XY:

163

AN XY:

74420

show subpopulations

African (AFR)

AF:

0.00725

AC:

301

AN:

41526

American (AMR)

AF:

0.000785

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.000208

AC:

AN:

4812

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68012

Other (OTH)

AF:

0.00142

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.512

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000994

Hom.:

Bravo

AF:

0.00298

ESP6500AA

AF:

0.00704

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000824

AC:

100

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.0000593

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Mucopolysaccharidosis type 6 (5)

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.051

BayesDel_addAF

Benign

-0.088

BayesDel_noAF

Uncertain

0.11

CADD

Benign

(source)

DANN

Benign

0.16

DEOGEN2

Uncertain

0.62

Eigen

Benign

-1.1

Eigen_PC

Benign

-0.98

FATHMM_MKL

Benign

0.33

LIST_S2

Benign

0.83

M_CAP

Benign

0.040

MetaRNN

Benign

0.013

MetaSVM

Uncertain

0.11

MutationAssessor

Benign

0.39

PhyloP100

2.7

PrimateAI

Benign

0.47

PROVEAN

Benign

4.4

REVEL

Uncertain

0.56

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0080

Vest4

0.72

MVP

0.81

MPC

0.29

ClinPred

0.0018

GERP RS

0.16

Varity_R

0.037

gMVP

0.71

Mutation Taster

=3/97

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over