rs1413561387

Variant names:

• chr5-78984989-G-A
• rs1413561387
• NM_000046.5:c.260C>T

Your query was ambiguous. Multiple possible variants found:

• chr5-78984989-G-A
• chr5-78984989-G-C

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1 PM2 PP2

The NM_000046.5(ARSB):​c.260C>T​(p.Thr87Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000659 in 151,774 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T87R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ARSB NM_000046.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.573
• Publications: 0 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: Uncertain_significance. The variant received 5 ACMG points.

• PM1: In a hotspot region, there are 16 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in NM_000046.5
• PM2: Very rare variant in population databases, with high coverage
• 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARSB	NM_000046.5	c.260C>T	p.Thr87Met	missense_variant	Exon 1 of 8	ENST00000264914.10	NP_000037.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARSB	ENST00000264914.10	c.260C>T	p.Thr87Met	missense_variant	Exon 1 of 8	1	NM_000046.5	ENSP00000264914.4
ARSB	ENST00000396151.7	c.260C>T	p.Thr87Met	missense_variant	Exon 2 of 8	1		ENSP00000379455.3
ARSB	ENST00000565165.2	c.260C>T	p.Thr87Met	missense_variant	Exon 1 of 5	1		ENSP00000456339.2
ARSB	ENST00000521117.1	c.*123C>T		downstream_gene_variant		3		ENSP00000428611.1

Frequencies

GnomAD3 genomes AF: 0.00000659 AC: 1 AN: 151774 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 7.24e-7 AC: 1 AN: 1382008 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 686958

African (AFR) AF: 0.00 AC: 0 AN: 28618

American (AMR) AF: 0.00 AC: 0 AN: 35130

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24050

East Asian (EAS) AF: 0.00 AC: 0 AN: 31832

South Asian (SAS) AF: 0.00 AC: 0 AN: 77512

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47734

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4682

European-Non Finnish (NFE) AF: 9.29e-7 AC: 1 AN: 1075964

Other (OTH) AF: 0.00 AC: 0 AN: 56486

GnomAD4 genome AF: 0.00000659 AC: 1 AN: 151774 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74126

African (AFR) AF: 0.00 AC: 0 AN: 41376

American (AMR) AF: 0.00 AC: 0 AN: 15246

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5144

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10512

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67884

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.71	D;.;.
Eigen	Uncertain	0.19
Eigen_PC	Benign	0.11
FATHMM_MKL	Benign	0.40	N
LIST_S2	Uncertain	0.96	D;D;D
M_CAP	Pathogenic	0.98	D
MetaRNN	Uncertain	0.74	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.5	M;M;.
PhyloP100		0.57
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-0.12	N;N;N
REVEL	Uncertain	0.60
Sift	Benign	0.047	D;D;D
Sift4G	Uncertain	0.036	D;D;D
Polyphen		0.68	P;.;.
Vest4		0.25
MutPred		0.80		Gain of phosphorylation at Y86 (P = 0.0972);Gain of phosphorylation at Y86 (P = 0.0972);Gain of phosphorylation at Y86 (P = 0.0972);
MVP		0.95
MPC		0.76
ClinPred		0.73	D
GERP RS		2.7
PromoterAI		-0.099	Neutral
Varity_R		0.19
gMVP		0.92
Mutation Taster		=58/42	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: rs1413561387; hg19: chr5-78280812;