rs6151412

chr22-50627172-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000487.6(ARSA):c.459C>T(p.His153=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0435 in 1,611,236 control chromosomes in the GnomAD database, including 1,938 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.056 (310 hom., cov: 33)
  • Exomes 𝑓: 0.042 (1628 hom.)
• Consequence: ARSA NM_000487.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -0.474

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BP6: Variant 22-50627172-G-A is Benign according to our data. Variant chr22-50627172-G-A is described in ClinVar as [Benign]. Clinvar id is 93123.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-50627172-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.474 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0994 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARSA	NM_000487.6	c.459C>T	p.His153=	synonymous_variant	2/8	ENST00000216124.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARSA	ENST00000216124.10	c.459C>T	p.His153=	synonymous_variant	2/8	1	NM_000487.6	P1

Frequencies

GnomAD3 genomes AF: 0.0561 AC: 8540 AN: 152182 Hom.: 309 Cov.: 33

Gnomad AFR AF: 0.102

Gnomad AMI AF: 0.128

Gnomad AMR AF: 0.0467

Gnomad ASJ AF: 0.0251

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00434

Gnomad FIN AF: 0.00997

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0462

Gnomad OTH AF: 0.0554

GnomAD3 exomes AF: 0.0338 AC: 8139 AN: 240752 Hom.: 235 AF XY: 0.0329 AC XY: 4335 AN XY: 131692

Gnomad AFR exome AF: 0.106

Gnomad AMR exome AF: 0.0275

Gnomad ASJ exome AF: 0.0222

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00638

Gnomad FIN exome AF: 0.0117

Gnomad NFE exome AF: 0.0445

Gnomad OTH exome AF: 0.0354

GnomAD4 exome AF: 0.0422 AC: 61597 AN: 1458936 Hom.: 1628 Cov.: 33 AF XY: 0.0409 AC XY: 29689 AN XY: 725454

Gnomad4 AFR exome AF: 0.106

Gnomad4 AMR exome AF: 0.0289

Gnomad4 ASJ exome AF: 0.0229

Gnomad4 EAS exome AF: 0.0000505

Gnomad4 SAS exome AF: 0.00657

Gnomad4 FIN exome AF: 0.0130

Gnomad4 NFE exome AF: 0.0470

Gnomad4 OTH exome AF: 0.0427

GnomAD4 genome AF: 0.0561 AC: 8548 AN: 152300 Hom.: 310 Cov.: 33 AF XY: 0.0530 AC XY: 3946 AN XY: 74476

Gnomad4 AFR AF: 0.102

Gnomad4 AMR AF: 0.0465

Gnomad4 ASJ AF: 0.0251

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00434

Gnomad4 FIN AF: 0.00997

Gnomad4 NFE AF: 0.0462

Gnomad4 OTH AF: 0.0549

Alfa AF: 0.0492 Hom.: 118

Bravo AF: 0.0612

Asia WGS AF: 0.00779 AC: 28 AN: 3478

EpiCase AF: 0.0456

EpiControl AF: 0.0469

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 24, 2013	- -
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	Clinical Genetics, Academic Medical Center	-	- -

Metachromatic leukodystrophy Benign:3

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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. -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 29, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

not provided Benign:2

Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Apr 18, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Citrullinemia Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
Cadd	Benign	1.0
Dann	Benign	0.48
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs6151412; hg19: chr22-51065600;