rs201168448

chr5-78985151-G-Achr5-78985151-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000046.5(ARSB):c.98C>T(p.Ala33Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0122 in 1,453,254 control chromosomes in the GnomAD database, including 149 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A33A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0098 (19 hom., cov: 33)
  • Exomes 𝑓: 0.012 (130 hom.)
• Consequence: ARSB NM_000046.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -0.567

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0036388934).
• BP6: Variant 5-78985151-G-A is Benign according to our data. Variant chr5-78985151-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 193036.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00982 (1488/151474) while in subpopulation AMR AF= 0.012 (183/15246). AF 95% confidence interval is 0.0111. There are 19 homozygotes in gnomad4. There are 820 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 19 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARSB	NM_000046.5	c.98C>T	p.Ala33Val	missense_variant	1/8	ENST00000264914.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARSB	ENST00000264914.10	c.98C>T	p.Ala33Val	missense_variant	1/8	1	NM_000046.5	P1
ARSB	ENST00000396151.7	c.98C>T	p.Ala33Val	missense_variant	2/8	1
ARSB	ENST00000565165.2	c.98C>T	p.Ala33Val	missense_variant	1/5	1
ARSB	ENST00000521117.1	c.98C>T	p.Ala33Val	missense_variant	2/2	3

Frequencies

GnomAD3 genomes AF: 0.00984 AC: 1489 AN: 151366 Hom.: 19 Cov.: 33

Gnomad AFR AF: 0.00233

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.0120

Gnomad ASJ AF: 0.00981

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000623

Gnomad FIN AF: 0.0344

Gnomad MID AF: 0.00955

Gnomad NFE AF: 0.0118

Gnomad OTH AF: 0.00480

GnomAD3 exomes AF: 0.0105 AC: 1087 AN: 103530 Hom.: 6 AF XY: 0.00991 AC XY: 592 AN XY: 59764

Gnomad AFR exome AF: 0.00203

Gnomad AMR exome AF: 0.00418

Gnomad ASJ exome AF: 0.0112

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000386

Gnomad FIN exome AF: 0.0336

Gnomad NFE exome AF: 0.0124

Gnomad OTH exome AF: 0.00921

GnomAD4 exome AF: 0.0124 AC: 16196 AN: 1301780 Hom.: 130 Cov.: 31 AF XY: 0.0120 AC XY: 7676 AN XY: 640686

Gnomad4 AFR exome AF: 0.00152

Gnomad4 AMR exome AF: 0.00522

Gnomad4 ASJ exome AF: 0.00983

Gnomad4 EAS exome AF: 0.0000337

Gnomad4 SAS exome AF: 0.000258

Gnomad4 FIN exome AF: 0.0287

Gnomad4 NFE exome AF: 0.0135

Gnomad4 OTH exome AF: 0.0121

GnomAD4 genome AF: 0.00982 AC: 1488 AN: 151474 Hom.: 19 Cov.: 33 AF XY: 0.0111 AC XY: 820 AN XY: 74040

Gnomad4 AFR AF: 0.00232

Gnomad4 AMR AF: 0.0120

Gnomad4 ASJ AF: 0.00981

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000624

Gnomad4 FIN AF: 0.0344

Gnomad4 NFE AF: 0.0118

Gnomad4 OTH AF: 0.00475

Alfa AF: 0.0102 Hom.: 2

Bravo AF: 0.00852

ESP6500AA AF: 0.00457 AC: 13

ESP6500EA AF: 0.0111 AC: 68

ExAC AF: 0.00757 AC: 822

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Mucopolysaccharidosis type 6 Benign:6

Benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 18, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	curation	Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova	Jan 01, 2018	Allele frequency greater than expected for disorder (BS1); Homozygotes reported in GnomAD (BS2); Classified benign by a reputable source (BP6) -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Oct 30, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2023	ARSB: BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 03, 2020	This variant is associated with the following publications: (PMID: 17458871, 21228398, 22133300) -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jun 16, 2016	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 19, 2014	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 10, 2021	- -

ARSB-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 23, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.090
Cadd	Benign	4.4
Dann	Benign	0.82
DEOGEN2	Benign	0.32	T;.;.;.
Eigen	Benign	-1.9
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.33	T;T;T;T
MetaRNN	Benign	0.0036	T;T;T;T
MetaSVM	Uncertain	-0.21	T
MutationAssessor	Benign	0.34	N;N;.;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-0.39	N;N;N;D
REVEL	Uncertain	0.35
Sift	Benign	0.76	T;T;T;.
Sift4G	Benign	0.31	T;T;T;.
Polyphen		0.0020	B;.;.;.
Vest4		0.54
MPC		1.5
ClinPred		0.0025	T
GERP RS		-1.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.026
gMVP		0.55

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

Other links and lift over

dbSNP: rs201168448; hg19: chr5-78280974; COSMIC: COSV99061553;