rs199476347

Variant names:

• chr22-50626246-C-T
• rs199476347
• NM_000487.6:c.887G>A

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_000487.6(ARSA):​c.887G>A​(p.Cys296Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000131 in 152,224 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 Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: 𝑓 0.000013 (0 hom., cov: 34)
• Consequence: ARSA NM_000487.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1 O:1
• Conservation: PhyloP100: 2.13

Genes affected

ARSA (HGNC:713): (arylsulfatase A) The protein encoded by this gene hydrolyzes cerebroside sulfate to cerebroside and sulfate. Defects in this gene lead to metachromatic leucodystrophy (MLD), a progressive demyelination disease which results in a variety of neurological symptoms and ultimately death. Alternatively spliced transcript variants have been described for this gene. [provided by RefSeq, Dec 2010]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.859
• PP5: Variant 22-50626246-C-T is Pathogenic according to our data. Variant chr22-50626246-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 68156.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1, not_provided=1}. Variant chr22-50626246-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARSA	NM_000487.6	c.887G>A	p.Cys296Tyr	missense_variant	Exon 5 of 8	ENST00000216124.10	NP_000478.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARSA	ENST00000216124.10	c.887G>A	p.Cys296Tyr	missense_variant	Exon 5 of 8	1	NM_000487.6	ENSP00000216124.5

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152224 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.0000482

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 35

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152224 Hom.: 0 Cov.: 34 AF XY: 0.0000134 AC XY: 1 AN XY: 74364

Gnomad4 AFR AF: 0.0000482

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1 Other:1

-

UniProtKB/Swiss-Prot

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Oct 11, 2024

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a damaging effect as C296Y had 0% enzyme activity compared to wild type, which is consistent with a loss of function mechanism (PMID: 15326627); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; Also known as p.C294Y; This variant is associated with the following publications: (PMID: 15326627) -

Metachromatic leukodystrophy Pathogenic:1

Sep 06, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 296 of the ARSA protein (p.Cys296Tyr). This variant is present in population databases (rs199476347, gnomAD 0.01%). This missense change has been observed in individual(s) with metachromatic leukodystrophy (PMID: 15326627; internal data). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as G1530A. ClinVar contains an entry for this variant (Variation ID: 68156). 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) indicates that this missense variant is expected to disrupt ARSA protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects ARSA function (PMID: 15326627). For these reasons, this variant has been classified as Pathogenic. -

not specified Uncertain:1

Jul 11, 2024

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: ARSA c.887G>A (p.Cys296Tyr) results in a non-conservative amino acid change in the encoded protein sequence. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 248784 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.887G>A has been reported in the literature in an individual affected with Juvenile Metachromatic Leukodystrophy (example: Berna_2004). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 15326627). ClinVar contains an entry for this variant (Variation ID: 68156). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.17
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.32	T;T;T;.;T
Eigen	Uncertain	0.20
Eigen_PC	Benign	0.22
FATHMM_MKL	Benign	0.73	D
LIST_S2	Uncertain	0.87	.;.;.;D;D
M_CAP	Pathogenic	0.30	D
MetaRNN	Pathogenic	0.86	D;D;D;D;D
MetaSVM	Uncertain	0.77	D
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-2.0	N;N;N;N;N
REVEL	Uncertain	0.62
Sift	Uncertain	0.029	D;D;D;D;D
Sift4G	Uncertain	0.033	D;D;D;T;D
Vest4		0.82
MVP		0.95
ClinPred		0.89	D
GERP RS		3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.92

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

LitVar

Other links and lift over

dbSNP: rs199476347; hg19: chr22-51064674;