chr22-50627218-G-A

Variant names:

• chr22-50627218-G-A
• rs74315462
• NM_000487.6:c.413C>T
• ARSA p.Pro138Leu

GermlineCancer (beta)

Variant summary

Our verdict is Pathogenic.

>+14 Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 18 classification points (ACMG Germline Pathogenicity v2019). PS3PM1PM2PM5PP3_StrongPP5_Strong

The NM_000487.6(ARSA):c.413C>T (p.Pro138Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.000000685 (AC=1) in the gnomAD database across 1,459,778 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.0000116. In-silico predictor (REVEL) classifies this variant as likely damaging/oncogenic. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic/Likely Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV001592679: Experimental studies have shown that this missense change affects ARSA function (PMID:7860068)." and additional evidence is available in ClinVar. A different missense at the same amino acid position has been reported as Pathogenic/Likely Pathogenic in ClinVar: p.P138T: Pathogenic (ClinVar VariationId 2138466, 1 star) Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.P138= (synonymous): Likely_benign (ClinVar VariationId 1091637, 1 star); p.P138= (synonymous): Likely_benign (ClinVar VariationId 797462, 1 star)

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: ARSA NM_000487.6 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3 U:1
• Conservation: PhyloP100: 6.71
• Publications: 5 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: Natera, ClinGen, Myriad Women's Health
• metachromatic leukodystrophy, juvenile form

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, PanelApp Australia, Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)

Classification according to ACMG Germline Pathogenicity v2019

Our verdict: Pathogenic. The variant received 18 points.

• PS3: Well-established functional study supports damaging effect (PS3); SCV001592679: Experimental studies have shown that this missense change affects ARSA function (PMID: 7860068).; SCV002073107: This variant has been reported to affect ARSA protein function (Kafert S et al, 1995).
• PM1: Missense neighbourhood hotspot (≥2 P/LP within ±8 AA, OR ≥ 5 vs. background) — PM1; In-domain: 0 pathogenic, 0 benign rare missense variants.; ±8 AA neighbourhood: 8 pathogenic, 0 benign (OR vs. background: 85.0).
• PM2: Very rare in gnomAD for AR/unknown gene (popmax AF < threshold/10) — PM2; GnomAD popmax AF = 0.0000116 — very rare for AR gene (threshold 0.001) — PM2 moderate.
• PM5: Different pathogenic missense at same AA residue in ClinVar (PM5); ClinVar contains a germline Pathogenic/Likely Pathogenic entry at the same amino acid position with a different amino acid change: p.P138T: Pathogenic (ClinVar VariationId 2138466, 1 star); Other variants at the same amino acid residue (not pathogenic): p.P138= (synonymous): Likely_benign (ClinVar VariationId 1091637, 1 star); p.P138= (synonymous): Likely_benign (ClinVar VariationId 797462, 1 star)
• PP3: Germline meta computational scorer (REVEL/MetaRNN/BayesDel) predicts damaging effect — strong evidence (PP3); Splicing verdict: not pathogenic.; Germline computational verdict: pathogenic (Strong).
• PP5: ClinVar 2-star pathogenic — strong (PP5); ClinVar germline classification: Pathogenic/Likely Pathogenic, 2 star(s).

Variant Effect in Transcripts

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

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARSA	NM_000487.6	MANE Select	c.413C>T	p.Pro138Leu	missense	Exon 2 of 8	NP_000478.3
	ARSA	NM_001085425.3		c.413C>T	p.Pro138Leu	missense	Exon 3 of 9	NP_001078894.2	A0A0C4DFZ2
	ARSA	NM_001085426.3		c.413C>T	p.Pro138Leu	missense	Exon 3 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.413C>T	p.Pro138Leu	missense	Exon 2 of 8	ENSP00000216124.5	A0A0C4DFZ2
	ARSA	ENST00000356098.9	TSL:1	c.413C>T	p.Pro138Leu	missense	Exon 3 of 9	ENSP00000348406.5	A0A0C4DFZ2
	ARSA	ENST00000395619.3	TSL:5	c.413C>T	p.Pro138Leu	missense	Exon 3 of 9	ENSP00000378981.3	A0A0C4DFZ2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000419 AC: 1 AN: 238454 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000562

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459778 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 726108

African (AFR) AF: 0.00 AC: 0 AN: 33460

American (AMR) AF: 0.00 AC: 0 AN: 44532

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26070

East Asian (EAS) AF: 0.00 AC: 0 AN: 39656

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86112

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52528

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111362

Other (OTH) AF: 0.00 AC: 0 AN: 60294

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	1	-	Metachromatic leukodystrophy (3)
1	-	-	METACHROMATIC LEUKODYSTROPHY, SEVERE (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.80
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.52
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.50	T
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.41	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
PhyloP100		6.7
PrimateAI	Uncertain	0.71	T
PROVEAN	Pathogenic	-8.3	D
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0020	D
gMVP		0.97
Mutation Taster		=0/100	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs74315462;

hg19: chr22-51065646;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar