rs743616

chr22-50625611-G-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 4P and 20B. PM1 PM5 BP4_Strong BP6_Very_Strong BA1

The NM_000487.6(ARSA):c.1178C>G(p.Thr393Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.518 in 1,612,938 control chromosomes in the GnomAD database, including 220,625 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/15 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T393G) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.48 (17902 hom., cov: 32)
  • Exomes 𝑓: 0.52 (202723 hom.)
• Consequence: ARSA NM_000487.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts U:1 B:13 O:1
• Conservation: PhyloP100: 0.122

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 -16 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_000487.6
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr22-50625611-GT-CC is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1308665.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=3, Uncertain_significance=2}.
• BP4: Computational evidence support a benign effect (MetaRNN=1.3175593E-5).
• BP6: Variant 22-50625611-G-C is Benign according to our data. Variant chr22-50625611-G-C is described in ClinVar as [Benign]. Clinvar id is 21184.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-50625611-G-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.535 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARSA	NM_000487.6	c.1178C>G	p.Thr393Ser	missense_variant	7/8	ENST00000216124.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARSA	ENST00000216124.10	c.1178C>G	p.Thr393Ser	missense_variant	7/8	1	NM_000487.6	P1

Frequencies

GnomAD3 genomes AF: 0.479 AC: 72763 AN: 151796 Hom.: 17887 Cov.: 32

Gnomad AFR AF: 0.390

Gnomad AMI AF: 0.647

Gnomad AMR AF: 0.455

Gnomad ASJ AF: 0.430

Gnomad EAS AF: 0.310

Gnomad SAS AF: 0.420

Gnomad FIN AF: 0.597

Gnomad MID AF: 0.367

Gnomad NFE AF: 0.540

Gnomad OTH AF: 0.456

GnomAD3 exomes AF: 0.480 AC: 120494 AN: 251106 Hom.: 29962 AF XY: 0.483 AC XY: 65650 AN XY: 135860

Gnomad AFR exome AF: 0.384

Gnomad AMR exome AF: 0.418

Gnomad ASJ exome AF: 0.424

Gnomad EAS exome AF: 0.291

Gnomad SAS exome AF: 0.423

Gnomad FIN exome AF: 0.594

Gnomad NFE exome AF: 0.540

Gnomad OTH exome AF: 0.498

GnomAD4 exome AF: 0.523 AC: 763470 AN: 1461024 Hom.: 202723 Cov.: 74 AF XY: 0.521 AC XY: 378298 AN XY: 726796

Gnomad4 AFR exome AF: 0.382

Gnomad4 AMR exome AF: 0.420

Gnomad4 ASJ exome AF: 0.417

Gnomad4 EAS exome AF: 0.343

Gnomad4 SAS exome AF: 0.428

Gnomad4 FIN exome AF: 0.595

Gnomad4 NFE exome AF: 0.546

Gnomad4 OTH exome AF: 0.493

GnomAD4 genome AF: 0.479 AC: 72803 AN: 151914 Hom.: 17902 Cov.: 32 AF XY: 0.481 AC XY: 35740 AN XY: 74256

Gnomad4 AFR AF: 0.390

Gnomad4 AMR AF: 0.454

Gnomad4 ASJ AF: 0.430

Gnomad4 EAS AF: 0.310

Gnomad4 SAS AF: 0.421

Gnomad4 FIN AF: 0.597

Gnomad4 NFE AF: 0.540

Gnomad4 OTH AF: 0.453

Alfa AF: 0.511 Hom.: 6579

Bravo AF: 0.463

TwinsUK AF: 0.540 AC: 2004

ALSPAC AF: 0.544 AC: 2095

ESP6500AA AF: 0.394 AC: 1736

ESP6500EA AF: 0.530 AC: 4560

ExAC AF: 0.483 AC: 58673

Asia WGS AF: 0.384 AC: 1337 AN: 3478

EpiCase AF: 0.520

EpiControl AF: 0.515

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:13 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Metachromatic leukodystrophy Benign:6 Other:1

Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Benign, no assertion criteria provided	curation	SingHealth Duke-NUS Institute of Precision Medicine	Jun 07, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 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. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 18, 2019	- -

not specified Benign:6

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
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	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
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)	Mar 16, 2015	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Uncertain:1 Benign:1

Uncertain significance, 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	This variant is associated with the following publications: (PMID: 31694723, 29961769, 11941485, 1670590, 20220177) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.34
Cadd	Benign	0.66
Dann	Benign	0.83
DEOGEN2	Benign	0.23	T;T;T;.;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.024	N
MetaRNN	Benign	0.000013	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	P;P;P;P;P;P;P
PrimateAI	Benign	0.36	T
PROVEAN	Benign	0.13	N;N;N;N;N
REVEL	Benign	0.29
Sift	Benign	0.47	T;T;T;T;T
Sift4G	Benign	0.41	T;T;T;T;T
Vest4		0.031
ClinPred		0.0040	T
GERP RS		-0.029
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.45

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs743616; hg19: chr22-51064039; COSMIC: COSV53350010; COSMIC: COSV53350010;