chr22-50625559-G-C

Position:

• chr22-50625559-G-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.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

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=-0.84).
• BP6: Variant 22-50625559-G-C is Benign according to our data. Variant chr22-50625559-G-C is described in ClinVar as [Benign]. Clinvar id is 93118.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-50625559-G-C is described in Lovd as [Benign].
• 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/exons	MANE	Protein	UniProt
ARSA	NM_000487.6	c.1210+20C>G		intron_variant		ENST00000216124.10	NP_000478.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARSA	ENST00000216124.10	c.1210+20C>G		intron_variant		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

GnomAD3 exomes AF: 0.802 AC: 200504 AN: 249936 Hom.: 81008 AF XY: 0.799 AC XY: 108363 AN XY: 135612

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 SAS exome AF: 0.809

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

Gnomad4 AFR exome AF: 0.725

Gnomad4 AMR exome AF: 0.858

Gnomad4 ASJ exome AF: 0.717

Gnomad4 EAS exome AF: 0.941

Gnomad4 SAS exome AF: 0.811

Gnomad4 FIN exome AF: 0.803

Gnomad4 NFE exome AF: 0.778

Gnomad4 OTH exome AF: 0.781

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

Gnomad4 AFR AF: 0.722

Gnomad4 AMR AF: 0.816

Gnomad4 ASJ AF: 0.712

Gnomad4 EAS AF: 0.973

Gnomad4 SAS AF: 0.827

Gnomad4 FIN AF: 0.808

Gnomad4 NFE AF: 0.771

Gnomad4 OTH AF: 0.757

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

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 21, 2016	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided Benign:4

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	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 22, 2015	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Metachromatic leukodystrophy Benign:2

Benign, criteria provided, single submitter	clinical testing	Pars Genome Lab	Jun 15, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	2.1
DANN	Benign	0.32
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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

Publications

LitVar

Other links and lift over

dbSNP: rs762674; hg19: chr22-51063987;