22-50625049-T-C

Position:

• chr22-50625049-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000487.6(ARSA):​c.*96A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.073 in 1,343,902 control chromosomes in the GnomAD database, including 4,090 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign,other (★★).

• Frequency:
  • Genomes: 𝑓 0.054 (278 hom., cov: 32)
  • Exomes 𝑓: 0.075 (3812 hom.)
• Consequence: ARSA NM_000487.6 3_prime_UTR
• Clinical Significance: Benign; other criteria provided, multiple submitters, no conflicts P:1 U:2 B:12 O:4
• Conservation: PhyloP100: 0.972

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BP6: Variant 22-50625049-T-C is Benign according to our data. Variant chr22-50625049-T-C is described in ClinVar as [Benign, other]. Clinvar id is 3049.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-50625049-T-C is described in Lovd as [Benign]. Variant chr22-50625049-T-C is described in Lovd as [Pathogenic].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.104 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARSA	NM_000487.6	c.*96A>G		3_prime_UTR_variant	8/8	ENST00000216124.10	NP_000478.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARSA	ENST00000216124	c.*96A>G		3_prime_UTR_variant	8/8	1	NM_000487.6	ENSP00000216124.5

Frequencies

GnomAD3 genomes AF: 0.0536 AC: 8153 AN: 152184 Hom.: 274 Cov.: 32

Gnomad AFR AF: 0.0127

Gnomad AMI AF: 0.0526

Gnomad AMR AF: 0.0502

Gnomad ASJ AF: 0.102

Gnomad EAS AF: 0.0188

Gnomad SAS AF: 0.112

Gnomad FIN AF: 0.0365

Gnomad MID AF: 0.111

Gnomad NFE AF: 0.0775

Gnomad OTH AF: 0.0592

GnomAD4 exome AF: 0.0755 AC: 89951 AN: 1191600 Hom.: 3812 Cov.: 19 AF XY: 0.0770 AC XY: 44704 AN XY: 580856

Gnomad4 AFR exome AF: 0.0121

Gnomad4 AMR exome AF: 0.0479

Gnomad4 ASJ exome AF: 0.106

Gnomad4 EAS exome AF: 0.0118

Gnomad4 SAS exome AF: 0.114

Gnomad4 FIN exome AF: 0.0372

Gnomad4 NFE exome AF: 0.0783

Gnomad4 OTH exome AF: 0.0720

GnomAD4 genome AF: 0.0536 AC: 8170 AN: 152302 Hom.: 278 Cov.: 32 AF XY: 0.0522 AC XY: 3890 AN XY: 74478

Gnomad4 AFR AF: 0.0127

Gnomad4 AMR AF: 0.0501

Gnomad4 ASJ AF: 0.102

Gnomad4 EAS AF: 0.0189

Gnomad4 SAS AF: 0.112

Gnomad4 FIN AF: 0.0365

Gnomad4 NFE AF: 0.0775

Gnomad4 OTH AF: 0.0662

Alfa AF: 0.0754 Hom.: 633

Bravo AF: 0.0516

Asia WGS AF: 0.0930 AC: 322 AN: 3478

ClinVar

Significance: Benign; other

Submissions summary: Pathogenic:1 Uncertain:2 Benign:12 Other:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Metachromatic leukodystrophy Uncertain:2 Benign:3 Other:3

other, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 08, 2019	- pseudodeficiency allele
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 10, 2021	- -
not provided, no classification provided	phenotyping only	GenomeConnect - Invitae Patient Insights Network	-	Variant interpreted as Benign and reported on 10-15-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -
Uncertain significance, no assertion criteria provided	curation	SingHealth Duke-NUS Institute of Precision Medicine	Jun 07, 2017	- -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 07, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not specified Benign:5

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not provided Benign:4 Other:1

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Oct 11, 2016	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 11, 2021	This variant is associated with the following publications: (PMID: 30026549, 26577183, 21648305, 2574462, 8897113, 8095918, 29961769) -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
other, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 24, 2018	- Variant classified as "other reportable" ??? variant is clinically benign (not associated with disease) but is reported when observed (e.g. pseudodeficiency alleles).

ARYLSULFATASE A PSEUDODEFICIENCY Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Aug 01, 1998

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	14
DANN	Benign	0.79

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs6151429; hg19: chr22-51063477;