rs74315481

Variant names:

• chr22-50625443-G-A
• rs74315481
• NM_000487.6:c.1232C>T

Your query was ambiguous. Multiple possible variants found:

• chr22-50625443-G-A
• chr22-50625443-G-C

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PS3 PM1 PP2 PP3 PP5_Very_Strong

The NM_000487.6(ARSA):​c.1232C>T​(p.Thr411Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000622 in 1,447,764 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV002113878: Experimental studies have shown that this missense change affects ARSA function (PMID:7909527)." and additional evidence is available in ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: ARSA NM_000487.6 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4 O:1
• Conservation: PhyloP100: 5.26
• Publications: 10 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: Pathogenic. The variant received 16 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV002113878: Experimental studies have shown that this missense change affects ARSA function (PMID: 7909527).; SCV005380313: The variant was absent in 238866 control chromosomes (gnomAD). c.1232C>T has been reported in the literature in individuals affected with Metachromatic Leukodystrophy (e.g. Hasegawa_1994, Fukutani_1999, Suzuki_2008, Miura_2010). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, finding that the variant results in 10%-<30% of normal ARSA activity (Hasegawa_1994). PMID: 7909527 Functional evidence evaluating an impact on protein function, finding that the variant results in 10%-<30% of normal ARSA activity (Hasegawa_1994). PMID: 7909527
• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 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.
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 22-50625443-G-A is Pathogenic according to our data. Variant chr22-50625443-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 3087.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.1232C>T	p.Thr411Ile	missense	Exon 8 of 8	NP_000478.3
	ARSA	NM_001085425.3		c.1232C>T	p.Thr411Ile	missense	Exon 9 of 9	NP_001078894.2	A0A0C4DFZ2
	ARSA	NM_001085426.3		c.1232C>T	p.Thr411Ile	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.1232C>T	p.Thr411Ile	missense	Exon 8 of 8	ENSP00000216124.5	A0A0C4DFZ2
	ARSA	ENST00000356098.9	TSL:1	c.1232C>T	p.Thr411Ile	missense	Exon 9 of 9	ENSP00000348406.5	A0A0C4DFZ2
	ARSA	ENST00000395619.3	TSL:5	c.1232C>T	p.Thr411Ile	missense	Exon 9 of 9	ENSP00000378981.3	A0A0C4DFZ2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000622 AC: 9 AN: 1447764 Hom.: 0 Cov.: 32 AF XY: 0.00000696 AC XY: 5 AN XY: 718444

African (AFR) AF: 0.00 AC: 0 AN: 33270

American (AMR) AF: 0.00 AC: 0 AN: 44232

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25150

East Asian (EAS) AF: 0.000228 AC: 9 AN: 39506

South Asian (SAS) AF: 0.00 AC: 0 AN: 84778

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51710

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5706

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1103598

Other (OTH) AF: 0.00 AC: 0 AN: 59814

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	Metachromatic leukodystrophy (4)
1	-	-	METACHROMATIC LEUKODYSTROPHY, MILD (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Benign	0.33	T
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.043	D
MetaRNN	Pathogenic	0.83	D
MetaSVM	Uncertain	-0.17	T
PhyloP100		5.3
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-2.0	N
REVEL	Pathogenic	0.66
Sift	Benign	0.30	T
Sift4G	Benign	0.074	T
Vest4		0.85
MVP		0.88
ClinPred		0.88	D
GERP RS		4.4
gMVP		0.70
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.55		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.55		Position offset: -6

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs74315481; hg19: chr22-51063871;