rs72762973

Variant names:

• chr5-78885754-T-C
• rs72762973
• NM_000046.5:c.972A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000046.5(ARSB):​c.972A>G​(p.Gly324Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0639 in 1,613,994 control chromosomes in the GnomAD database, including 3,846 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. G324G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.053 (312 hom., cov: 32)
  • Exomes 𝑓: 0.065 (3534 hom.)
• Consequence: ARSB NM_000046.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.285
• Publications: 10 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 5-78885754-T-C is Benign according to our data. Variant chr5-78885754-T-C is described in ClinVar as Benign. ClinVar VariationId is 92357.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.285 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0722 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARSB	NM_000046.5	MANE Select	c.972A>G	p.Gly324Gly	synonymous	Exon 5 of 8	NP_000037.2
	ARSB	NM_198709.3		c.972A>G	p.Gly324Gly	synonymous	Exon 6 of 8	NP_942002.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARSB	ENST00000264914.10	TSL:1 MANE Select	c.972A>G	p.Gly324Gly	synonymous	Exon 5 of 8	ENSP00000264914.4
	ARSB	ENST00000396151.7	TSL:1	c.972A>G	p.Gly324Gly	synonymous	Exon 6 of 8	ENSP00000379455.3
	ARSB	ENST00000565165.2	TSL:1	c.972A>G	p.Gly324Gly	synonymous	Exon 5 of 5	ENSP00000456339.2

Frequencies

GnomAD3 genomes AF: 0.0533 AC: 8103 AN: 151984 Hom.: 312 Cov.: 32

Gnomad AFR AF: 0.0131

Gnomad AMI AF: 0.117

Gnomad AMR AF: 0.0463

Gnomad ASJ AF: 0.0490

Gnomad EAS AF: 0.000579

Gnomad SAS AF: 0.0143

Gnomad FIN AF: 0.129

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.0739

Gnomad OTH AF: 0.0489

GnomAD2 exomes AF: 0.0529 AC: 13290 AN: 251348 AF XY: 0.0521

Gnomad AFR exome AF: 0.0139

Gnomad AMR exome AF: 0.0314

Gnomad ASJ exome AF: 0.0514

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.112

Gnomad NFE exome AF: 0.0725

Gnomad OTH exome AF: 0.0590

GnomAD4 exome AF: 0.0650 AC: 95022 AN: 1461892 Hom.: 3534 Cov.: 35 AF XY: 0.0637 AC XY: 46297 AN XY: 727246

African (AFR) AF: 0.0108 AC: 363 AN: 33480

American (AMR) AF: 0.0340 AC: 1521 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0522 AC: 1365 AN: 26136

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39700

South Asian (SAS) AF: 0.0141 AC: 1219 AN: 86258

European-Finnish (FIN) AF: 0.108 AC: 5789 AN: 53418

Middle Eastern (MID) AF: 0.0220 AC: 127 AN: 5768

European-Non Finnish (NFE) AF: 0.0730 AC: 81143 AN: 1112012

Other (OTH) AF: 0.0578 AC: 3491 AN: 60396

GnomAD4 genome AF: 0.0533 AC: 8100 AN: 152102 Hom.: 312 Cov.: 32 AF XY: 0.0537 AC XY: 3995 AN XY: 74334

African (AFR) AF: 0.0131 AC: 544 AN: 41528

American (AMR) AF: 0.0462 AC: 706 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.0490 AC: 170 AN: 3468

East Asian (EAS) AF: 0.000580 AC: 3 AN: 5172

South Asian (SAS) AF: 0.0143 AC: 69 AN: 4812

European-Finnish (FIN) AF: 0.129 AC: 1365 AN: 10568

Middle Eastern (MID) AF: 0.0408 AC: 12 AN: 294

European-Non Finnish (NFE) AF: 0.0739 AC: 5022 AN: 67968

Other (OTH) AF: 0.0484 AC: 102 AN: 2108

Alfa AF: 0.0619 Hom.: 169

Bravo AF: 0.0459

Asia WGS AF: 0.00693 AC: 26 AN: 3478

EpiCase AF: 0.0706

EpiControl AF: 0.0664

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	7.8
DANN	Benign	0.60
PhyloP100		-0.28
Mutation Taster		=100/0	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: rs72762973; hg19: chr5-78181577; COSMIC: COSV53729712;