rs201168448

Variant names:

• chr5-78985151-G-A
• rs201168448
• NM_000046.5:c.98C>T

Your query was ambiguous. Multiple possible variants found:

• chr5-78985151-G-A
• chr5-78985151-G-T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2 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. 12/21 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:13
• Conservation: PhyloP100: -0.567
• Publications: 6 publications found

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

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• 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=0.0036388934).
• BP6: Variant 5-78985151-G-A is Benign according to our data. Variant chr5-78985151-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId 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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 19 AR gene

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.98C>T	p.Ala33Val	missense	Exon 1 of 8	NP_000037.2
	ARSB	NM_198709.3		c.98C>T	p.Ala33Val	missense	Exon 2 of 8	NP_942002.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARSB	ENST00000264914.10	TSL:1 MANE Select	c.98C>T	p.Ala33Val	missense	Exon 1 of 8	ENSP00000264914.4
	ARSB	ENST00000396151.7	TSL:1	c.98C>T	p.Ala33Val	missense	Exon 2 of 8	ENSP00000379455.3
	ARSB	ENST00000565165.2	TSL:1	c.98C>T	p.Ala33Val	missense	Exon 1 of 5	ENSP00000456339.2

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

GnomAD2 exomes AF: 0.0105 AC: 1087 AN: 103530 AF XY: 0.00991

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 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

African (AFR) AF: 0.00152 AC: 41 AN: 27046

American (AMR) AF: 0.00522 AC: 131 AN: 25084

Ashkenazi Jewish (ASJ) AF: 0.00983 AC: 213 AN: 21660

East Asian (EAS) AF: 0.0000337 AC: 1 AN: 29704

South Asian (SAS) AF: 0.000258 AC: 17 AN: 65912

European-Finnish (FIN) AF: 0.0287 AC: 1168 AN: 40698

Middle Eastern (MID) AF: 0.000900 AC: 4 AN: 4444

European-Non Finnish (NFE) AF: 0.0135 AC: 13978 AN: 1034166

Other (OTH) AF: 0.0121 AC: 643 AN: 53066

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

African (AFR) AF: 0.00232 AC: 96 AN: 41356

American (AMR) AF: 0.0120 AC: 183 AN: 15246

Ashkenazi Jewish (ASJ) AF: 0.00981 AC: 34 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5124

South Asian (SAS) AF: 0.000624 AC: 3 AN: 4810

European-Finnish (FIN) AF: 0.0344 AC: 358 AN: 10416

Middle Eastern (MID) AF: 0.00685 AC: 2 AN: 292

European-Non Finnish (NFE) AF: 0.0118 AC: 798 AN: 67748

Other (OTH) AF: 0.00475 AC: 10 AN: 2104

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

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	Mucopolysaccharidosis type 6 (6)
-	-	4	not provided (4)
-	-	2	not specified (2)
-	-	1	ARSB-related disorder (1)

Computational scores

Source: dbNSFP v4.9

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
MetaRNN	Benign	0.0036	T
MetaSVM	Uncertain	-0.21	T
MutationAssessor	Benign	0.34	N
PhyloP100		-0.57
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-0.39	N
REVEL	Uncertain	0.35
Sift	Benign	0.76	T
Sift4G	Benign	0.31	T
Polyphen		0.0020	B
Vest4		0.54
MPC		1.5
ClinPred		0.0025	T
GERP RS		-1.4
PromoterAI		-0.046	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.026
gMVP		0.55
Mutation Taster		=95/5	polymorphism

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

Other links and lift over

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