22-50625182-C-T

Variant names:

• chr22-50625182-C-T
• rs6151428
• NM_000487.6:c.1493G>A

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 3P and 20B. PM1 PP2 BP4_Strong BP6_Very_Strong BA1

The NM_000487.6(ARSA):​c.1493G>A​(p.Arg498His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0388 in 1,594,468 control chromosomes in the GnomAD database, including 1,572 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R498P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.053 (303 hom., cov: 32)
  • Exomes 𝑓: 0.037 (1269 hom.)
• Consequence: ARSA NM_000487.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 1.43
• Publications: 13 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: G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -17 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, 11 uncertain in NM_000487.6
• 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=0.0019086301).
• BP6: Variant 22-50625182-C-T is Benign according to our data. Variant chr22-50625182-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 93120.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0976 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.1493G>A	p.Arg498His	missense	Exon 8 of 8	NP_000478.3
	ARSA	NM_001085425.3		c.1493G>A	p.Arg498His	missense	Exon 9 of 9	NP_001078894.2	A0A0C4DFZ2
	ARSA	NM_001085426.3		c.1493G>A	p.Arg498His	missense	Exon 9 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.1493G>A	p.Arg498His	missense	Exon 8 of 8	ENSP00000216124.5	A0A0C4DFZ2
	ARSA	ENST00000356098.9	TSL:1	c.1493G>A	p.Arg498His	missense	Exon 9 of 9	ENSP00000348406.5	A0A0C4DFZ2
	ARSA	ENST00000395619.3	TSL:5	c.1493G>A	p.Arg498His	missense	Exon 9 of 9	ENSP00000378981.3	A0A0C4DFZ2

Frequencies

GnomAD3 genomes AF: 0.0530 AC: 8071 AN: 152204 Hom.: 301 Cov.: 32

Gnomad AFR AF: 0.100

Gnomad AMI AF: 0.129

Gnomad AMR AF: 0.0454

Gnomad ASJ AF: 0.0222

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00434

Gnomad FIN AF: 0.00876

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0411

Gnomad OTH AF: 0.0535

GnomAD2 exomes AF: 0.0305 AC: 6634 AN: 217596 AF XY: 0.0296

Gnomad AFR exome AF: 0.104

Gnomad AMR exome AF: 0.0261

Gnomad ASJ exome AF: 0.0187

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00909

Gnomad NFE exome AF: 0.0396

Gnomad OTH exome AF: 0.0303

GnomAD4 exome AF: 0.0373 AC: 53731 AN: 1442146 Hom.: 1269 Cov.: 32 AF XY: 0.0362 AC XY: 25901 AN XY: 715820

African (AFR) AF: 0.106 AC: 3510 AN: 33194

American (AMR) AF: 0.0275 AC: 1175 AN: 42702

Ashkenazi Jewish (ASJ) AF: 0.0191 AC: 487 AN: 25466

East Asian (EAS) AF: 0.0000766 AC: 3 AN: 39170

South Asian (SAS) AF: 0.00655 AC: 553 AN: 84374

European-Finnish (FIN) AF: 0.0104 AC: 517 AN: 49700

Middle Eastern (MID) AF: 0.0220 AC: 121 AN: 5500

European-Non Finnish (NFE) AF: 0.0409 AC: 45121 AN: 1102596

Other (OTH) AF: 0.0377 AC: 2244 AN: 59444

GnomAD4 genome AF: 0.0530 AC: 8080 AN: 152322 Hom.: 303 Cov.: 32 AF XY: 0.0500 AC XY: 3724 AN XY: 74494

African (AFR) AF: 0.100 AC: 4160 AN: 41560

American (AMR) AF: 0.0453 AC: 694 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.0222 AC: 77 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5186

South Asian (SAS) AF: 0.00434 AC: 21 AN: 4834

European-Finnish (FIN) AF: 0.00876 AC: 93 AN: 10618

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.0411 AC: 2795 AN: 68020

Other (OTH) AF: 0.0529 AC: 112 AN: 2116

Alfa AF: 0.0330 Hom.: 57

Bravo AF: 0.0583

TwinsUK AF: 0.0421 AC: 156

ALSPAC AF: 0.0389 AC: 150

ESP6500AA AF: 0.0884 AC: 384

ESP6500EA AF: 0.0381 AC: 325

ExAC AF: 0.0297 AC: 3586

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	3	Metachromatic leukodystrophy (3)
-	-	3	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	9.4
DANN	Benign	0.91
DEOGEN2	Benign	0.22	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.18	T
MetaRNN	Benign	0.0019	T
MetaSVM	Benign	-1.1	T
PhyloP100		1.4
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-0.11	N
REVEL	Benign	0.23
Sift	Benign	0.58	T
Sift4G	Benign	0.50	T
Vest4		0.051
ClinPred		0.00099	T
GERP RS		-0.95
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.43
Mutation Taster		=81/19	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: rs6151428; hg19: chr22-51063610;