NM_000487.6:c.433C>G

Variant names:

• chr22-50627198-G-C
• rs199476373
• NM_000487.6:c.433C>G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Moderate

The NM_000487.6(ARSA):​c.433C>G​(p.Arg145Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,460,614 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R145Q) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ARSA NM_000487.6 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1 O:1
• Conservation: PhyloP100: 3.78

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 Pathogenic. Variant got 10 ACMG points.

• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_000487.6
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr22-50627197-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 899762.We mark this variant Likely_pathogenic, oryginal submissions are: {not_provided=1, Uncertain_significance=1, Likely_pathogenic=1}.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.85
• PP5: Variant 22-50627198-G-C is Pathogenic according to our data. Variant chr22-50627198-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 68133.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr22-50627198-G-C is described in Lovd as [Pathogenic]. Variant chr22-50627198-G-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARSA	NM_000487.6	c.433C>G	p.Arg145Gly	missense_variant	Exon 2 of 8	ENST00000216124.10	NP_000478.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARSA	ENST00000216124.10	c.433C>G	p.Arg145Gly	missense_variant	Exon 2 of 8	1	NM_000487.6	ENSP00000216124.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460614 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 726532

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: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Metachromatic leukodystrophy Pathogenic:1

Oct 01, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine with glycine at codon 145 of the ARSA protein (p.Arg145Gly). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and glycine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to segregate with metachromatic leukodystrophy in a family (PMID: 11020646). This variant is also known as Arg143Gly. ClinVar contains an entry for this variant (Variation ID: 68133). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

not provided Other:1

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UniProtKB/Swiss-Prot

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.27
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Benign	0.31	T;T;T;.;T
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Uncertain	0.92	.;.;.;D;D
M_CAP	Uncertain	0.19	D
MetaRNN	Pathogenic	0.85	D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-1.5	N;N;N;N;N
REVEL	Pathogenic	0.66
Sift	Benign	0.15	T;T;T;T;T
Sift4G	Benign	0.40	T;T;T;T;T
Vest4		0.83
MVP		0.91
ClinPred		0.81	D
GERP RS		4.7
gMVP		0.88

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs199476373; hg19: chr22-51065626;