chr5-78839372-G-C

Variant names:

• chr5-78839372-G-C
• rs200793396
• NM_000046.5:c.1197C>G

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_000046.5(ARSB):​c.1197C>G​(p.Phe399Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,550 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 Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: ARSB NM_000046.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 1.42

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 Pathogenic. Variant got 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.968
• PP5: Variant 5-78839372-G-C is Pathogenic according to our data. Variant chr5-78839372-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 559688.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARSB	NM_000046.5	c.1197C>G	p.Phe399Leu	missense_variant	Exon 6 of 8	ENST00000264914.10	NP_000037.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARSB	ENST00000264914.10	c.1197C>G	p.Phe399Leu	missense_variant	Exon 6 of 8	1	NM_000046.5	ENSP00000264914.4
ARSB	ENST00000396151.7	c.1197C>G	p.Phe399Leu	missense_variant	Exon 7 of 8	1		ENSP00000379455.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000199 AC: 5 AN: 251354 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135836

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000272

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461550 Hom.: 0 Cov.: 30 AF XY: 0.00000413 AC XY: 3 AN XY: 727092

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Mucopolysaccharidosis type 6 Pathogenic:5

Mar 26, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 26, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 399 of the ARSB protein (p.Phe399Leu). This variant is present in population databases (rs200793396, gnomAD 0.02%). This missense change has been observed in individual(s) with mucopolysaccharidosis type VI (PMID: 11802522, 18486607, 25190157). ClinVar contains an entry for this variant (Variation ID: 559688). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ARSB protein function. For these reasons, this variant has been classified as Pathogenic. -

Nov 04, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: ARSB c.1197C>G (p.Phe399Leu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 251354 control chromosomes. c.1197C>G has been reported in the literature in multiple homozygous and compound heterozygous individuals affected with Mucopolysaccharidosis Type VI (Maroteaux-Lamy Syndrome) (Yang_2001, Lin_2008, Zheng_2014, He_2021, Fang_2022). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 34813777, 33985463, 18486607, 11802522, 25190157). ClinVar contains an entry for this variant (Variation ID: 559688). Based on the evidence outlined above, the variant was classified as pathogenic. -

Jan 01, 2018

Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

In vitro functional studies supportive of a damaging effect on the gene product (low to no ARSB activity in homozygotes; PS3); Very low frequency in ExAC (PM2) -

Sep 10, 2018

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The ARSB c.1197C>G (p.Phe399Leu) missense variant has been reported in five studies and is found in a total of seven individuals with mucopolysaccharidosis, type VI, including in one in a homozygous state and in six in a compound heterozygous state, including one sibling pair (Yang et al. 2001; Ching-Wan et al. 2004; Lin et al. 2008; But et al. 2011; Zheng et al. 2014). The p.Phe399Leu variant was also found in a heterozygous state in two unaffected parents (Ching-Wan et al. 2004). The p.Phe399Leu variant was absent from 150 control subjects and is reported at a frequency of 0.000174 in the East Asian population of the Genome Aggregation Database. Based on the evidence, the p.Phe399Leu variant is classified as pathogenic for mucopolysaccharidosis. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Pathogenic	0.30
CADD	Benign	14
DANN	Benign	0.89
DEOGEN2	Uncertain	0.48	T;.
Eigen	Benign	-0.75
Eigen_PC	Benign	-0.88
FATHMM_MKL	Benign	0.48	N
LIST_S2	Benign	0.85	D;D
M_CAP	Pathogenic	0.38	D
MetaRNN	Pathogenic	0.97	D;D
MetaSVM	Uncertain	0.38	D
MutationAssessor	Uncertain	2.2	M;M
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-2.2	N;N
REVEL	Uncertain	0.64
Sift	Benign	0.12	T;T
Sift4G	Benign	0.27	T;T
Polyphen		0.75	P;.
Vest4		0.80
MutPred		0.80		Loss of sheet (P = 0.0228);Loss of sheet (P = 0.0228);
MVP		0.93
MPC		0.39
ClinPred		0.21	T
GERP RS		-3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.30
gMVP		0.82

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs200793396; hg19: chr5-78135195;