22-50625049-T-C

Variant names:

• chr22-50625049-T-C
• rs6151429
• NM_000487.6:c.*96A>G

Variant summary

Our verdict is Benign. The variant received -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:13 O:4
• Conservation: PhyloP100: 0.972
• Publications: 80 publications found

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]

ARSA Gene-Disease associations (from GenCC):

• metachromatic leukodystrophy

  Inheritance: AR Classification: DEFINITIVE Submitted by: Myriad Women’s Health, ClinGen
• metachromatic leukodystrophy, juvenile form

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 3049.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
ARSA	NM_000487.6	c.*96A>G		3_prime_UTR_variant	Exon 8 of 8	ENST00000216124.10	NP_000478.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARSA	ENST00000216124.10	c.*96A>G		3_prime_UTR_variant	Exon 8 of 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

African (AFR) AF: 0.0121 AC: 318 AN: 26244

American (AMR) AF: 0.0479 AC: 971 AN: 20266

Ashkenazi Jewish (ASJ) AF: 0.106 AC: 1948 AN: 18336

East Asian (EAS) AF: 0.0118 AC: 403 AN: 34288

South Asian (SAS) AF: 0.114 AC: 6928 AN: 60862

European-Finnish (FIN) AF: 0.0372 AC: 1122 AN: 30154

Middle Eastern (MID) AF: 0.132 AC: 457 AN: 3468

European-Non Finnish (NFE) AF: 0.0783 AC: 74180 AN: 947640

Other (OTH) AF: 0.0720 AC: 3624 AN: 50342

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

African (AFR) AF: 0.0127 AC: 527 AN: 41566

American (AMR) AF: 0.0501 AC: 767 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.102 AC: 353 AN: 3468

East Asian (EAS) AF: 0.0189 AC: 98 AN: 5190

South Asian (SAS) AF: 0.112 AC: 542 AN: 4828

European-Finnish (FIN) AF: 0.0365 AC: 388 AN: 10620

Middle Eastern (MID) AF: 0.112 AC: 33 AN: 294

European-Non Finnish (NFE) AF: 0.0775 AC: 5274 AN: 68008

Other (OTH) AF: 0.0662 AC: 140 AN: 2116

Alfa AF: 0.0703 Hom.: 1462

Bravo AF: 0.0516

Asia WGS AF: 0.0930 AC: 322 AN: 3478

ClinVar

Significance: Benign; other

Submissions summary: Pathogenic:1 Uncertain:2 Benign:13 Other:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Metachromatic leukodystrophy Uncertain:2 Benign:4 Other:3

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Jan 08, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: other

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- pseudodeficiency allele

Jun 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 07, 2017

SingHealth Duke-NUS Institute of Precision Medicine

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: curation

- -

Jan 07, 2020

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

GenomeConnect - Invitae Patient Insights Network

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

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. -

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

May 28, 2019

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 06, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

- -

not specified Benign:5

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:4 Other:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Oct 11, 2016

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 24, 2018

Eurofins Ntd Llc (ga)

Significance: other

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- Variant classified as "other reportable" ??? variant is clinically benign (not associated with disease) but is reported when observed (e.g. pseudodeficiency alleles).

Nov 11, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 30026549, 26577183, 21648305, 2574462, 8897113, 8095918, 29961769) -

-

Clinical Genetics, Academic Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

ARYLSULFATASE A PSEUDODEFICIENCY Pathogenic:1

Aug 01, 1998

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	14
DANN	Benign	0.79
PhyloP100		0.97
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs6151429; hg19: chr22-51063477;