NM_000046.5:c.271T>G

Variant names:

• chr5-78984978-A-C
• NM_000046.5:c.271T>G

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PP3_Strong

The NM_000046.5(ARSB):​c.271T>G​(p.Cys91Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000000733 in 1,364,156 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.3e-7 (0 hom.)
• Consequence: ARSB NM_000046.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.84

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a binding_site via 3-oxoalanine (size 0) in uniprot entity ARSB_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.987

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARSB	NM_000046.5	c.271T>G	p.Cys91Gly	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.271T>G	p.Cys91Gly	missense_variant	Exon 1 of 8	1	NM_000046.5	ENSP00000264914.4
ARSB	ENST00000396151.7	c.271T>G	p.Cys91Gly	missense_variant	Exon 2 of 8	1		ENSP00000379455.3
ARSB	ENST00000565165.2	c.271T>G	p.Cys91Gly	missense_variant	Exon 1 of 5	1		ENSP00000456339.2
ARSB	ENST00000521117.1	c.*134T>G		downstream_gene_variant		3		ENSP00000428611.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.33e-7 AC: 1 AN: 1364156 Hom.: 0 Cov.: 31 AF XY: 0.00000148 AC XY: 1 AN XY: 677412

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.38e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Mucopolysaccharidosis type 6 Uncertain:1

Aug 02, 2023

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.64	D
BayesDel_noAF	Pathogenic	0.68
CADD	Pathogenic	32
DANN	Uncertain	0.97
DEOGEN2	Pathogenic	0.97	D;.;.
Eigen	Pathogenic	0.72
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.93	D;D;D
M_CAP	Pathogenic	0.99	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.3	H;H;.
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-11	D;D;D
REVEL	Pathogenic	0.95
Sift	Uncertain	0.0030	D;D;D
Sift4G	Uncertain	0.0070	D;D;D
Polyphen		1.0	D;.;.
Vest4		0.84
MutPred		0.93		Gain of disorder (P = 0.0051);Gain of disorder (P = 0.0051);Gain of disorder (P = 0.0051);
MVP		1.0
MPC		0.61
ClinPred		1.0	D
GERP RS		3.4
Varity_R		0.97
gMVP		0.99

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-78280801;