rs2071421

Variant names:

• chr22-50625988-T-C
• rs2071421
• NM_000487.6:c.1055A>G

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

The NM_000487.6(ARSA):​c.1055A>G​(p.Asn352Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.143 in 1,576,320 control chromosomes in the GnomAD database, including 18,971 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign,other (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N352H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.19 (3436 hom., cov: 34)
  • Exomes 𝑓: 0.14 (15535 hom.)
• Consequence: ARSA NM_000487.6 missense
• Clinical Significance: Benign/Likely benign; other criteria provided, multiple submitters, no conflicts U:1 B:16 O:2
• Conservation: PhyloP100: 1.46
• Publications: 89 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: Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 159 curated pathogenic missense variants (we use a threshold of 10). The gene has 11 curated benign missense variants. Gene score misZ: 0.38013 (below the threshold of 3.09). Trascript score misZ: -0.56919 (below the threshold of 3.09). GenCC associations: The gene is linked to metachromatic leukodystrophy, juvenile form, metachromatic leukodystrophy.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0014927089).
• BP6: Variant 22-50625988-T-C is Benign according to our data. Variant chr22-50625988-T-C is described in ClinVar as Benign/Likely_benign|other. ClinVar VariationId is 3050.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.324 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000487.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARSA	NM_000487.6	MANE Select	c.1055A>G	p.Asn352Ser	missense	Exon 6 of 8	NP_000478.3
	ARSA	NM_001085425.3		c.1055A>G	p.Asn352Ser	missense	Exon 7 of 9	NP_001078894.2	A0A0C4DFZ2
	ARSA	NM_001085426.3		c.1055A>G	p.Asn352Ser	missense	Exon 7 of 9	NP_001078895.2	A0A0C4DFZ2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARSA	ENST00000216124.10	TSL:1 MANE Select	c.1055A>G	p.Asn352Ser	missense	Exon 6 of 8	ENSP00000216124.5	A0A0C4DFZ2
	ARSA	ENST00000356098.9	TSL:1	c.1055A>G	p.Asn352Ser	missense	Exon 7 of 9	ENSP00000348406.5	A0A0C4DFZ2
	ARSA	ENST00000395619.3	TSL:5	c.1055A>G	p.Asn352Ser	missense	Exon 7 of 9	ENSP00000378981.3	A0A0C4DFZ2

Frequencies

GnomAD3 genomes AF: 0.192 AC: 29196 AN: 152016 Hom.: 3416 Cov.: 34

Gnomad AFR AF: 0.329

Gnomad AMI AF: 0.181

Gnomad AMR AF: 0.240

Gnomad ASJ AF: 0.138

Gnomad EAS AF: 0.164

Gnomad SAS AF: 0.145

Gnomad FIN AF: 0.0660

Gnomad MID AF: 0.177

Gnomad NFE AF: 0.126

Gnomad OTH AF: 0.187

GnomAD2 exomes AF: 0.165 AC: 31196 AN: 188538 AF XY: 0.158

Gnomad AFR exome AF: 0.337

Gnomad AMR exome AF: 0.298

Gnomad ASJ exome AF: 0.141

Gnomad EAS exome AF: 0.173

Gnomad FIN exome AF: 0.0631

Gnomad NFE exome AF: 0.127

Gnomad OTH exome AF: 0.158

GnomAD4 exome AF: 0.138 AC: 196120 AN: 1424186 Hom.: 15535 Cov.: 37 AF XY: 0.137 AC XY: 96518 AN XY: 704492

African (AFR) AF: 0.351 AC: 11649 AN: 33196

American (AMR) AF: 0.294 AC: 10794 AN: 36716

Ashkenazi Jewish (ASJ) AF: 0.139 AC: 3530 AN: 25342

East Asian (EAS) AF: 0.164 AC: 6322 AN: 38548

South Asian (SAS) AF: 0.147 AC: 11988 AN: 81334

European-Finnish (FIN) AF: 0.0646 AC: 3239 AN: 50162

Middle Eastern (MID) AF: 0.199 AC: 1136 AN: 5700

European-Non Finnish (NFE) AF: 0.127 AC: 138764 AN: 1094010

Other (OTH) AF: 0.147 AC: 8698 AN: 59178

GnomAD4 genome AF: 0.192 AC: 29259 AN: 152134 Hom.: 3436 Cov.: 34 AF XY: 0.188 AC XY: 14013 AN XY: 74368

African (AFR) AF: 0.329 AC: 13656 AN: 41500

American (AMR) AF: 0.240 AC: 3674 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.138 AC: 477 AN: 3468

East Asian (EAS) AF: 0.164 AC: 843 AN: 5142

South Asian (SAS) AF: 0.146 AC: 704 AN: 4826

European-Finnish (FIN) AF: 0.0660 AC: 700 AN: 10608

Middle Eastern (MID) AF: 0.184 AC: 54 AN: 294

European-Non Finnish (NFE) AF: 0.126 AC: 8580 AN: 67970

Other (OTH) AF: 0.192 AC: 406 AN: 2112

Alfa AF: 0.152 Hom.: 5516

Bravo AF: 0.215

TwinsUK AF: 0.138 AC: 510

ALSPAC AF: 0.119 AC: 458

ESP6500AA AF: 0.299 AC: 1305

ESP6500EA AF: 0.123 AC: 1050

ExAC AF: 0.132 AC: 15352

Asia WGS AF: 0.195 AC: 680 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign; other

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	8	Metachromatic leukodystrophy (9)
-	-	5	not specified (5)
-	-	3	not provided (4)
-	1	-	Metachromatic leukodystrophy, juvenile type (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Uncertain	-0.080
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.30	T
Eigen	Benign	-0.088
Eigen_PC	Benign	0.082
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.87	D
MetaRNN	Benign	0.0015	T
MetaSVM	Benign	-1.2	T
PhyloP100		1.5
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.26
Sift	Benign	0.23	T
Sift4G	Benign	0.28	T
Vest4		0.15
ClinPred		0.011	T
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.46
Mutation Taster		=95/5	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs2071421; hg19: chr22-51064416; COSMIC: COSV53349851; COSMIC: COSV53349851;