5-78885654-C-T

Variant names:

• chr5-78885654-C-T
• rs1065757
• NM_000046.5:c.1072G>A

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 3P and 20B. PM1 PP2 BP4_Strong BP6_Very_Strong BA1

The NM_000046.5(ARSB):​c.1072G>A​(p.Val358Met) variant causes a missense change. The variant allele was found at a frequency of 0.413 in 1,613,786 control chromosomes in the GnomAD database, including 144,405 homozygotes. In-silico tool predicts 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. V358L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.34 (10960 hom., cov: 31)
  • Exomes 𝑓: 0.42 (133445 hom.)
• Consequence: ARSB NM_000046.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts U:1 B:11
• Conservation: PhyloP100: 4.93
• Publications: 60 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.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 3 uncertain in NM_000046.5
• 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=2.8827786E-4).
• BP6: Variant 5-78885654-C-T is Benign according to our data. Variant chr5-78885654-C-T is described in ClinVar as Benign. ClinVar VariationId is 92350.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.434 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.1072G>A	p.Val358Met	missense	Exon 5 of 8	NP_000037.2
	ARSB	NM_198709.3		c.1072G>A	p.Val358Met	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.1072G>A	p.Val358Met	missense	Exon 5 of 8	ENSP00000264914.4	P15848-1
	ARSB	ENST00000396151.7	TSL:1	c.1072G>A	p.Val358Met	missense	Exon 6 of 8	ENSP00000379455.3	P15848-2
	ARSB	ENST00000565165.2	TSL:1	c.1072G>A	p.Val358Met	missense	Exon 5 of 5	ENSP00000456339.2	A0A2U3U034

Frequencies

GnomAD3 genomes AF: 0.345 AC: 52361 AN: 151812 Hom.: 10965 Cov.: 31

Gnomad AFR AF: 0.109

Gnomad AMI AF: 0.485

Gnomad AMR AF: 0.404

Gnomad ASJ AF: 0.337

Gnomad EAS AF: 0.380

Gnomad SAS AF: 0.259

Gnomad FIN AF: 0.600

Gnomad MID AF: 0.364

Gnomad NFE AF: 0.438

Gnomad OTH AF: 0.340

GnomAD2 exomes AF: 0.399 AC: 100122 AN: 251208 AF XY: 0.396

Gnomad AFR exome AF: 0.103

Gnomad AMR exome AF: 0.434

Gnomad ASJ exome AF: 0.343

Gnomad EAS exome AF: 0.391

Gnomad FIN exome AF: 0.586

Gnomad NFE exome AF: 0.440

Gnomad OTH exome AF: 0.407

GnomAD4 exome AF: 0.420 AC: 613553 AN: 1461856 Hom.: 133445 Cov.: 71 AF XY: 0.415 AC XY: 301543 AN XY: 727226

African (AFR) AF: 0.0966 AC: 3233 AN: 33480

American (AMR) AF: 0.427 AC: 19083 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.340 AC: 8886 AN: 26136

East Asian (EAS) AF: 0.374 AC: 14858 AN: 39700

South Asian (SAS) AF: 0.257 AC: 22180 AN: 86258

European-Finnish (FIN) AF: 0.578 AC: 30846 AN: 53408

Middle Eastern (MID) AF: 0.330 AC: 1904 AN: 5768

European-Non Finnish (NFE) AF: 0.439 AC: 488620 AN: 1111992

Other (OTH) AF: 0.396 AC: 23943 AN: 60396

GnomAD4 genome AF: 0.345 AC: 52364 AN: 151930 Hom.: 10960 Cov.: 31 AF XY: 0.354 AC XY: 26249 AN XY: 74248

African (AFR) AF: 0.108 AC: 4489 AN: 41466

American (AMR) AF: 0.404 AC: 6172 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.337 AC: 1168 AN: 3470

East Asian (EAS) AF: 0.380 AC: 1950 AN: 5138

South Asian (SAS) AF: 0.260 AC: 1252 AN: 4820

European-Finnish (FIN) AF: 0.600 AC: 6325 AN: 10542

Middle Eastern (MID) AF: 0.350 AC: 103 AN: 294

European-Non Finnish (NFE) AF: 0.438 AC: 29746 AN: 67922

Other (OTH) AF: 0.340 AC: 717 AN: 2106

Alfa AF: 0.395 Hom.: 38156

Bravo AF: 0.325

TwinsUK AF: 0.421 AC: 1562

ALSPAC AF: 0.413 AC: 1591

ESP6500AA AF: 0.114 AC: 504

ESP6500EA AF: 0.432 AC: 3719

ExAC AF: 0.391 AC: 47428

Asia WGS AF: 0.264 AC: 920 AN: 3478

EpiCase AF: 0.419

EpiControl AF: 0.425

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	Mucopolysaccharidosis type 6 (5)
-	-	4	not specified (4)
-	1	2	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Uncertain	-0.030
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.81	D
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.94	D
MetaRNN	Benign	0.00029	T
MetaSVM	Benign	-1.5	T
MutationAssessor	Benign	0.67	N
PhyloP100		4.9
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-2.2	N
REVEL	Uncertain	0.46
Sift	Benign	0.10	T
Sift4G	Benign	0.13	T
Polyphen		1.0	D
Vest4		0.24
MPC		0.81
ClinPred		0.017	T
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.58
gMVP		0.82
Mutation Taster		=91/9	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: rs1065757; hg19: chr5-78181477; COSMIC: COSV53719568;