rs74315481

Positions:

• chr22-50625443-G-A

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2 PP3 PP5_Very_Strong

The NM_000487.6(ARSA):​c.1232C>T​(p.Thr411Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000622 in 1,447,764 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: 0.0000062 (0 hom.)
• Consequence: ARSA NM_000487.6 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4 O:1
• Conservation: PhyloP100: 5.26

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 11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 22-50625443-G-A is Pathogenic according to our data. Variant chr22-50625443-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3087.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-50625443-G-A is described in Lovd as [Pathogenic]. Variant chr22-50625443-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARSA	NM_000487.6	c.1232C>T	p.Thr411Ile	missense_variant	8/8	ENST00000216124.10	NP_000478.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARSA	ENST00000216124.10	c.1232C>T	p.Thr411Ile	missense_variant	8/8	1	NM_000487.6	ENSP00000216124	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000622 AC: 9 AN: 1447764 Hom.: 0 Cov.: 32 AF XY: 0.00000696 AC XY: 5 AN XY: 718444

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000228

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

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Metachromatic leukodystrophy Pathogenic:3 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 23, 2024	Variant summary: ARSA c.1232C>T (p.Thr411Ile) results in a non-conservative amino acid change in the encoded protein sequence. Two of four in-silico tools predict a benign effect of the variant on protein function. Two computational tools predict a significant impact on normal splicing, suggesting the variant strengthens a cryptic 3' acceptor site in the exon 27 bp away from the canonical splice site. At least one publication reports experimental evidence that this variant affects mRNA splicing, resulting in both normal and aberrant transcript with a 27 bp deletion from the usual exon 8 splice acceptor site. The variant was absent in 238866 control chromosomes (gnomAD). c.1232C>T has been reported in the literature in individuals affected with Metachromatic Leukodystrophy (e.g. Hasegawa_1994, Fukutani_1999, Suzuki_2008, Miura_2010). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, finding that the variant results in 10%-<30% of normal ARSA activity (Hasegawa_1994). The following publications have been ascertained in the context of this evaluation (PMID: 7909527, 18832844, 22798296, 10459747). ClinVar contains an entry for this variant (Variation ID: 3087). Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 10, 2023	For these reasons, this variant has been classified as Pathogenic. Studies have shown that this missense change results in the activation of a cryptic splice site in exon 8 (PMID: 7909527). Experimental studies have shown that this missense change affects ARSA function (PMID: 7909527). Advanced 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 at Invitae 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 ARSA protein function. ClinVar contains an entry for this variant (Variation ID: 3087). This variant is also known as p.Thr409Ile. This missense change has been observed in individual(s) with metachromatic leukodystrophy (PMID: 7909527, 18832844, 19154224, 21265945, 22798296). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 411 of the ARSA protein (p.Thr411Ile). RNA analysis indicates that this missense change induces altered splicing and likely results in the loss of 9 amino acid residue(s), but is expected to preserve the integrity of the reading-frame. -
not provided, no classification provided	literature only	GeneReviews	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Nov 12, 2019	NM_000487.5(ARSA):c.1232C>T(T411I) is classified as likely pathogenic in the context of metachromatic leukodystrophy. Sources cited for classification include the following: PMID 18832844, 22798296, 21265945, 19154224, 10459747 and 7909527. Classification of NM_000487.5(ARSA):c.1232C>T(T411I) is based on the following criteria: This variant has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. -

Metachromatic leukodystrophy, mild Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 01, 1994

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Benign	0.33	T;T;T;.;T
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.78	.;.;.;T;T
M_CAP	Benign	0.043	D
MetaRNN	Pathogenic	0.83	D;D;D;D;D
MetaSVM	Uncertain	-0.17	T
MutationTaster	Benign	1.0	A;A;A;A;A;A;A
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-2.0	N;N;N;N;N
REVEL	Pathogenic	0.66
Sift	Benign	0.30	T;T;T;T;T
Sift4G	Benign	0.074	T;T;T;D;T
Vest4		0.85
MVP		0.88
ClinPred		0.88	D
GERP RS		4.4
gMVP		0.70

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.55		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.55		Position offset: -6

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

Publications

LitVar

Other links and lift over

dbSNP: rs74315481; hg19: chr22-51063871;