rs6151415

chr22-50626933-C-A

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BA1

The NM_000487.6(ARSA):c.585G>T(p.Trp195Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0685 in 1,613,172 control chromosomes in the GnomAD database, including 4,413 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.051 (275 hom., cov: 33)
  • Exomes 𝑓: 0.070 (4138 hom.)
• Consequence: ARSA NM_000487.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 1.05

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 -18 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 9 uncertain in NM_000487.6
• BP4: Computational evidence support a benign effect (MetaRNN=0.004769802).
• BP6: Variant 22-50626933-C-A is Benign according to our data. Variant chr22-50626933-C-A is described in ClinVar as [Benign]. Clinvar id is 93125.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-50626933-C-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0754 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARSA	NM_000487.6	c.585G>T	p.Trp195Cys	missense_variant	3/8	ENST00000216124.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARSA	ENST00000216124.10	c.585G>T	p.Trp195Cys	missense_variant	3/8	1	NM_000487.6	P1

Frequencies

GnomAD3 genomes AF: 0.0511 AC: 7779 AN: 152216 Hom.: 276 Cov.: 33

Gnomad AFR AF: 0.0150

Gnomad AMI AF: 0.0833

Gnomad AMR AF: 0.0340

Gnomad ASJ AF: 0.0810

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0151

Gnomad FIN AF: 0.0780

Gnomad MID AF: 0.0665

Gnomad NFE AF: 0.0772

Gnomad OTH AF: 0.0507

GnomAD3 exomes AF: 0.0529 AC: 13189 AN: 249174 Hom.: 491 AF XY: 0.0535 AC XY: 7243 AN XY: 135288

Gnomad AFR exome AF: 0.0127

Gnomad AMR exome AF: 0.0277

Gnomad ASJ exome AF: 0.0750

Gnomad EAS exome AF: 0.000164

Gnomad SAS exome AF: 0.0222

Gnomad FIN exome AF: 0.0752

Gnomad NFE exome AF: 0.0768

Gnomad OTH exome AF: 0.0586

GnomAD4 exome AF: 0.0703 AC: 102707 AN: 1460838 Hom.: 4138 Cov.: 34 AF XY: 0.0691 AC XY: 50188 AN XY: 726720

Gnomad4 AFR exome AF: 0.0110

Gnomad4 AMR exome AF: 0.0281

Gnomad4 ASJ exome AF: 0.0691

Gnomad4 EAS exome AF: 0.000151

Gnomad4 SAS exome AF: 0.0224

Gnomad4 FIN exome AF: 0.0718

Gnomad4 NFE exome AF: 0.0806

Gnomad4 OTH exome AF: 0.0601

GnomAD4 genome AF: 0.0511 AC: 7778 AN: 152334 Hom.: 275 Cov.: 33 AF XY: 0.0502 AC XY: 3738 AN XY: 74496

Gnomad4 AFR AF: 0.0150

Gnomad4 AMR AF: 0.0339

Gnomad4 ASJ AF: 0.0810

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.0153

Gnomad4 FIN AF: 0.0780

Gnomad4 NFE AF: 0.0772

Gnomad4 OTH AF: 0.0502

Alfa AF: 0.0709 Hom.: 701

Bravo AF: 0.0458

TwinsUK AF: 0.0747 AC: 277

ALSPAC AF: 0.0825 AC: 318

ESP6500AA AF: 0.0170 AC: 75

ESP6500EA AF: 0.0771 AC: 663

ExAC AF: 0.0527 AC: 6402

Asia WGS AF: 0.00808 AC: 28 AN: 3478

EpiCase AF: 0.0796

EpiControl AF: 0.0787

ClinVar

Significance: Benign

Submissions summary: Benign:12

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, no assertion criteria provided	clinical testing	Clinical Genetics, Academic 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	Eurofins Ntd Llc (ga)	Nov 23, 2015	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Metachromatic leukodystrophy Benign:4

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 29, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Pars Genome Lab	Jun 15, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
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 provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 31836585, 28670130, 8897113) -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jul 25, 2017	- -

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_addAF	Benign	-0.26	T
BayesDel_noAF	Uncertain	-0.080
Cadd	Pathogenic	26
Dann	Uncertain	0.99
DEOGEN2	Benign	0.23	T;T;T;.;T
Eigen	Benign	0.0048
Eigen_PC	Benign	0.041
FATHMM_MKL	Benign	0.70	D
MetaRNN	Benign	0.0048	T;T;T;T;T
MetaSVM	Benign	-0.32	T
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-0.73	N;N;N;N;N
REVEL	Uncertain	0.42
Sift	Benign	0.036	D;D;D;D;D
Sift4G	Uncertain	0.032	D;D;D;T;D
Vest4		0.49
ClinPred		0.010	T
GERP RS		3.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.90

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs6151415; hg19: chr22-51065361; COSMIC: COSV53350176; COSMIC: COSV53350176;