NM_000046.5:c.1126G>A

Variant names:

• chr5-78885600-C-T
• rs1071598
• NM_000046.5:c.1126G>A

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 3P and 20B. PM5 PP2 BP4_Strong BP6_Very_Strong BA1

The NM_000046.5(ARSB):​c.1126G>A​(p.Val376Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.16 in 1,613,742 control chromosomes in the GnomAD database, including 22,375 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 Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V376E) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.14 (1673 hom., cov: 32)
  • Exomes 𝑓: 0.16 (20702 hom.)
• Consequence: ARSB NM_000046.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 2.24
• Publications: 32 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: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen, Illumina, G2P

ACMG classification

Our verdict: Benign. The variant received -17 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr5-78885599-A-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 559675.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=0.0023964942).
• BP6: Variant 5-78885600-C-T is Benign according to our data. Variant chr5-78885600-C-T is described in ClinVar as Benign. ClinVar VariationId is 92351.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.184 is higher than 0.05.

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.1126G>A	p.Val376Met	missense	Exon 5 of 8	NP_000037.2
	ARSB	NM_198709.3		c.1126G>A	p.Val376Met	missense	Exon 6 of 8	NP_942002.1	P15848-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARSB	ENST00000264914.10	TSL:1 MANE Select	c.1126G>A	p.Val376Met	missense	Exon 5 of 8	ENSP00000264914.4	P15848-1
	ARSB	ENST00000396151.7	TSL:1	c.1126G>A	p.Val376Met	missense	Exon 6 of 8	ENSP00000379455.3	P15848-2
	ARSB	ENST00000565165.2	TSL:1	c.1126G>A	p.Val376Met	missense	Exon 5 of 5	ENSP00000456339.2	A0A2U3U034

Frequencies

GnomAD3 genomes AF: 0.135 AC: 20560 AN: 151988 Hom.: 1671 Cov.: 32

Gnomad AFR AF: 0.0669

Gnomad AMI AF: 0.229

Gnomad AMR AF: 0.189

Gnomad ASJ AF: 0.255

Gnomad EAS AF: 0.0158

Gnomad SAS AF: 0.189

Gnomad FIN AF: 0.113

Gnomad MID AF: 0.203

Gnomad NFE AF: 0.165

Gnomad OTH AF: 0.172

GnomAD2 exomes AF: 0.153 AC: 38291 AN: 250944 AF XY: 0.155

Gnomad AFR exome AF: 0.0633

Gnomad AMR exome AF: 0.204

Gnomad ASJ exome AF: 0.241

Gnomad EAS exome AF: 0.0141

Gnomad FIN exome AF: 0.115

Gnomad NFE exome AF: 0.163

Gnomad OTH exome AF: 0.166

GnomAD4 exome AF: 0.163 AC: 237977 AN: 1461636 Hom.: 20702 Cov.: 32 AF XY: 0.164 AC XY: 119573 AN XY: 727118

African (AFR) AF: 0.0636 AC: 2128 AN: 33474

American (AMR) AF: 0.205 AC: 9164 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.245 AC: 6392 AN: 26136

East Asian (EAS) AF: 0.00824 AC: 327 AN: 39700

South Asian (SAS) AF: 0.182 AC: 15739 AN: 86256

European-Finnish (FIN) AF: 0.115 AC: 6127 AN: 53198

Middle Eastern (MID) AF: 0.202 AC: 1168 AN: 5768

European-Non Finnish (NFE) AF: 0.168 AC: 187170 AN: 1112000

Other (OTH) AF: 0.162 AC: 9762 AN: 60382

GnomAD4 genome AF: 0.135 AC: 20568 AN: 152106 Hom.: 1673 Cov.: 32 AF XY: 0.134 AC XY: 9990 AN XY: 74344

African (AFR) AF: 0.0667 AC: 2770 AN: 41502

American (AMR) AF: 0.189 AC: 2890 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.255 AC: 884 AN: 3466

East Asian (EAS) AF: 0.0158 AC: 82 AN: 5174

South Asian (SAS) AF: 0.189 AC: 911 AN: 4822

European-Finnish (FIN) AF: 0.113 AC: 1198 AN: 10584

Middle Eastern (MID) AF: 0.214 AC: 63 AN: 294

European-Non Finnish (NFE) AF: 0.165 AC: 11206 AN: 67978

Other (OTH) AF: 0.169 AC: 356 AN: 2108

Alfa AF: 0.154 Hom.: 6484

Bravo AF: 0.137

TwinsUK AF: 0.172 AC: 638

ALSPAC AF: 0.172 AC: 661

ESP6500AA AF: 0.0701 AC: 309

ESP6500EA AF: 0.171 AC: 1473

ExAC AF: 0.146 AC: 17767

Asia WGS AF: 0.118 AC: 413 AN: 3478

EpiCase AF: 0.169

EpiControl AF: 0.168

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	3	Mucopolysaccharidosis type 6 (3)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	15
DANN	Uncertain	0.98
DEOGEN2	Benign	0.39	T
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.28
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.73	T
MetaRNN	Benign	0.0024	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	1.9	L
PhyloP100		2.2
PrimateAI	Uncertain	0.48	T
PROVEAN	Benign	-1.2	N
REVEL	Uncertain	0.30
Sift	Benign	0.14	T
Sift4G	Benign	0.23	T
Polyphen		0.83	P
Vest4		0.060
MPC		0.37
ClinPred		0.011	T
GERP RS		0.60
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.074
gMVP		0.81
Mutation Taster		=98/2	polymorphism (auto)

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: rs1071598; hg19: chr5-78181423; COSMIC: COSV53721518;