rs375493957

Positions:

• chr22-50627645-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PS1 PM1 PM2 PM5 BP4

The NM_000487.6(ARSA):​c.135C>A​(p.Ser45Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000022 in 1,408,000 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S45G) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000022 (0 hom.)
• Consequence: ARSA NM_000487.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• Conservation: PhyloP100: -0.100

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 Likely_pathogenic. Variant got 9 ACMG points.

• PS1: Transcript NM_000487.6 (ARSA) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 2847035
• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 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 chr22-50627647-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2990837.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.29022777).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARSA	NM_000487.6	c.135C>A	p.Ser45Arg	missense_variant	1/8	ENST00000216124.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARSA	ENST00000216124.10	c.135C>A	p.Ser45Arg	missense_variant	1/8	1	NM_000487.6	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000120 AC: 2 AN: 166846 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 88660

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000301

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000220 AC: 31 AN: 1408000 Hom.: 0 Cov.: 33 AF XY: 0.0000201 AC XY: 14 AN XY: 695370

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: 0.0000286

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.000143 Hom.: 0

Bravo AF: 0.0000151

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000234 AC: 2

ExAC AF: 0.00000856 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Metachromatic leukodystrophy Uncertain:3

Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Aug 23, 2022	This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 45 of the ARSA protein (p.Ser45Arg). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with metachromatic leukodystrophy (PMID: 12809637). This variant is also known as S43R. ClinVar contains an entry for this variant (Variation ID: 555715). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Dec 28, 2017	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Dec 27, 2022

Variant summary: ARSA c.135C>A (p.Ser45Arg) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 166846 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant, c.135C>A (published as c.129C>A (S43R)), has been reported in the literature in 2 siblings who had decreased ARSA enzyme activity measured in leukocytes and excess sulfatide excretion (Rafi_2003). While one of these individuals presented with cognitive decline and psychiatric problems at age 42, the other was asymptomatic at age 40, however the variant of interest was described to be found in cis with the frequent pseudodeficiency (Pd) allele (Rafi_2003). Therefore, these data do not allow clear conclusions about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jul 18, 2019

Reported, as S43R using alternate nomenclature, with second ARSA variant in 2 siblings, one with cognitive decline, dementia, and leukodystrophy at age 42 and the other asymptomatic at age 40; however phase of variants was not established (Rafi et al., 2003); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 12809637) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Benign	15
DANN	Uncertain	0.99
DEOGEN2	Benign	0.35	T;T;T;T
Eigen	Benign	-0.77
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.25	N
LIST_S2	Uncertain	0.96	.;.;.;D
M_CAP	Pathogenic	0.52	D
MetaRNN	Benign	0.29	T;T;T;T
MetaSVM	Pathogenic	1.0	D
MutationTaster	Benign	0.82	D;D;D;D;D;D;D
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-2.6	D;D;D;D
REVEL	Uncertain	0.63
Sift	Uncertain	0.0090	D;D;D;D
Sift4G	Uncertain	0.0060	D;D;D;D
Vest4		0.78
MVP		0.55
ClinPred		0.59	D
GERP RS		-10
gMVP		0.87

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: rs375493957; hg19: chr22-51066073;