chr22-50626878-C-G

Position:

• chr22-50626878-C-G

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM2 PM5 PP3 PP5_Very_Strong

The NM_000487.6(ARSA):​c.640G>C​(p.Ala214Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,108 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A214V) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ARSA NM_000487.6 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2 O:2
• Conservation: PhyloP100: 2.73

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 13 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr22-50626877-G-A is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.782
• PP5: Variant 22-50626878-C-G is Pathogenic according to our data. Variant chr22-50626878-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 68145.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-50626878-C-G is described in Lovd as [Pathogenic]. Variant chr22-50626878-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARSA	NM_000487.6	c.640G>C	p.Ala214Pro	missense_variant	3/8	ENST00000216124.10	NP_000478.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARSA	ENST00000216124.10	c.640G>C	p.Ala214Pro	missense_variant	3/8	1	NM_000487.6	ENSP00000216124.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461108 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 726834

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Metachromatic leukodystrophy Pathogenic:2 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 14, 2022	This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 214 of the ARSA protein (p.Ala214Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with metachromatic leukodystrophy (PMID: 18786133). This variant is also known as p.Ala212Pro. ClinVar contains an entry for this variant (Variation ID: 68145). 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) performed at Invitae indicates that this missense variant is expected to disrupt ARSA protein function. Experimental studies have shown that this missense change affects ARSA function (PMID: 18693274, 19606494). This variant disrupts the p.Ala214 amino acid residue in ARSA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7906588, 9090526, 9192271, 14517960, 26462614). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Jul 27, 2021	- -
not provided, no classification provided	in vitro	Gelb Laboratory, University of Washington	-	- -

not provided Other:1

not provided, no classification provided

literature only

UniProtKB/Swiss-Prot

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.34	T;T;T;.;T
Eigen	Uncertain	0.26
Eigen_PC	Benign	0.20
FATHMM_MKL	Benign	0.41	N
LIST_S2	Benign	0.80	.;.;.;T;T
M_CAP	Pathogenic	0.54	D
MetaRNN	Pathogenic	0.78	D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-1.8	N;N;N;N;N
REVEL	Pathogenic	0.67
Sift	Benign	0.16	T;T;T;T;T
Sift4G	Benign	0.24	T;T;T;T;T
Vest4		0.83
MVP		0.91
ClinPred		0.89	D
GERP RS		5.4
gMVP		0.93

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs199476341; hg19: chr22-51065306;