NM_000487.6:c.1210+20C>G

Variant names:

• chr22-50625559-G-C
• rs762674
• NM_000487.6:c.1210+20C>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.1210+20C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.784 in 1,609,658 control chromosomes in the GnomAD database, including 496,254 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.77 (45461 hom., cov: 30)
  • Exomes 𝑓: 0.79 (450793 hom.)
• Consequence: ARSA NM_000487.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -0.430
• Publications: 9 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=-0.84).
• BP6: Variant 22-50625559-G-C is Benign according to our data. Variant chr22-50625559-G-C is described in ClinVar as Benign. ClinVar VariationId is 93118.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.951 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARSA	NM_000487.6	c.1210+20C>G		intron_variant	Intron 7 of 7	ENST00000216124.10	NP_000478.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARSA	ENST00000216124.10	c.1210+20C>G		intron_variant	Intron 7 of 7	1	NM_000487.6	ENSP00000216124.5

Frequencies

GnomAD3 genomes AF: 0.772 AC: 117085 AN: 151596 Hom.: 45420 Cov.: 30

Gnomad AFR AF: 0.722

Gnomad AMI AF: 0.872

Gnomad AMR AF: 0.816

Gnomad ASJ AF: 0.712

Gnomad EAS AF: 0.974

Gnomad SAS AF: 0.826

Gnomad FIN AF: 0.808

Gnomad MID AF: 0.677

Gnomad NFE AF: 0.771

Gnomad OTH AF: 0.754

GnomAD2 exomes AF: 0.802 AC: 200504 AN: 249936 AF XY: 0.799

Gnomad AFR exome AF: 0.722

Gnomad AMR exome AF: 0.863

Gnomad ASJ exome AF: 0.722

Gnomad EAS exome AF: 0.979

Gnomad FIN exome AF: 0.805

Gnomad NFE exome AF: 0.772

Gnomad OTH exome AF: 0.792

GnomAD4 exome AF: 0.786 AC: 1145347 AN: 1457946 Hom.: 450793 Cov.: 44 AF XY: 0.786 AC XY: 570285 AN XY: 725484

African (AFR) AF: 0.725 AC: 24233 AN: 33406

American (AMR) AF: 0.858 AC: 38380 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.717 AC: 18688 AN: 26066

East Asian (EAS) AF: 0.941 AC: 37331 AN: 39682

South Asian (SAS) AF: 0.811 AC: 69917 AN: 86218

European-Finnish (FIN) AF: 0.803 AC: 41927 AN: 52196

Middle Eastern (MID) AF: 0.709 AC: 4085 AN: 5760

European-Non Finnish (NFE) AF: 0.778 AC: 863729 AN: 1109658

Other (OTH) AF: 0.781 AC: 47057 AN: 60254

GnomAD4 genome AF: 0.772 AC: 117182 AN: 151712 Hom.: 45461 Cov.: 30 AF XY: 0.777 AC XY: 57635 AN XY: 74136

African (AFR) AF: 0.722 AC: 29853 AN: 41320

American (AMR) AF: 0.816 AC: 12468 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.712 AC: 2468 AN: 3464

East Asian (EAS) AF: 0.973 AC: 4984 AN: 5120

South Asian (SAS) AF: 0.827 AC: 3973 AN: 4806

European-Finnish (FIN) AF: 0.808 AC: 8517 AN: 10546

Middle Eastern (MID) AF: 0.677 AC: 199 AN: 294

European-Non Finnish (NFE) AF: 0.771 AC: 52329 AN: 67870

Other (OTH) AF: 0.757 AC: 1596 AN: 2108

Alfa AF: 0.762 Hom.: 7837

Bravo AF: 0.771

Asia WGS AF: 0.895 AC: 3109 AN: 3474

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

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

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 21, 2016

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:4

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 22, 2015

Mayo Clinic Laboratories, Mayo Clinic

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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

- -

Metachromatic leukodystrophy Benign:2

Jun 15, 2021

Pars Genome Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	2.1
DANN	Benign	0.32
PhyloP100		-0.43
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs762674; hg19: chr22-51063987;