rs398123419

chr22-50626052-C-Achr22-50626052-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_000487.6(ARSA):c.991G>T(p.Glu331Ter) variant causes a stop gained change. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ARSA NM_000487.6 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 4.67

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 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 22-50626052-C-A is Pathogenic according to our data. Variant chr22-50626052-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 93129.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-50626052-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARSA	NM_000487.6	c.991G>T	p.Glu331Ter	stop_gained	6/8	ENST00000216124.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARSA	ENST00000216124.10	c.991G>T	p.Glu331Ter	stop_gained	6/8	1	NM_000487.6	P1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1440670 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 714506

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: 0.00

GnomAD4 genome Cov.: 34

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Metachromatic leukodystrophy Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 23, 2020	Variant summary: ARSA c.991G>T (p.Glu331X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 212420 control chromosomes (gnomAD). c.991G>T has been reported in the literature in at least an individual affected with Metachromatic Leukodystrophy (Bertelli_2005). These data do not allow any conclusion about variant significance. ARSA activity from patient (who was compound heterozygous for the variant) derived leukocytes was found to be 6.7nm/h/mg (Bertelli_2005). One ClinVar submitter (evaluation after 2014) cite the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Nov 20, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jun 20, 2022	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 93129). This variant is also known as p.Glu329Ter. This premature translational stop signal has been observed in individual(s) with metachromatic leukodystrophy (PMID: 16678723). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Glu331*) in the ARSA gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ARSA are known to be pathogenic (PMID: 8962139, 10477432). -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Nov 26, 2012

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.63
Cadd	Pathogenic	43
Dann	Uncertain	1.0
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.98	D
MutationTaster	Benign	1.0	A;A;A;A;A;A;A
Vest4		0.93
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs398123419; hg19: chr22-51064480;