chr22-50627171-C-T

Variant names:

• chr22-50627171-C-T
• rs199476365
• NM_000487.6:c.460G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1 PM2 PM5 PP2 PP5_Moderate

The NM_000487.6(ARSA):​c.460G>A​(p.Asp154Asn) variant causes a missense change. The variant allele was found at a frequency of 0.0000048 in 1,458,652 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D154H) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: ARSA NM_000487.6 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 5.94
• Publications: 2 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: Likely_pathogenic. The variant received 9 ACMG points.

• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 16 uncertain in NM_000487.6
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr22-50627171-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1937349.
• 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.
• PP5: Variant 22-50627171-C-T is Pathogenic according to our data. Variant chr22-50627171-C-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1411623.Status of the report is criteria_provided_single_submitter, 1 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.460G>A	p.Asp154Asn	missense	Exon 2 of 8	NP_000478.3
	ARSA	NM_001085425.3		c.460G>A	p.Asp154Asn	missense	Exon 3 of 9	NP_001078894.2	A0A0C4DFZ2
	ARSA	NM_001085426.3		c.460G>A	p.Asp154Asn	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.460G>A	p.Asp154Asn	missense	Exon 2 of 8	ENSP00000216124.5	A0A0C4DFZ2
	ARSA	ENST00000356098.9	TSL:1	c.460G>A	p.Asp154Asn	missense	Exon 3 of 9	ENSP00000348406.5	A0A0C4DFZ2
	ARSA	ENST00000395619.3	TSL:5	c.460G>A	p.Asp154Asn	missense	Exon 3 of 9	ENSP00000378981.3	A0A0C4DFZ2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000832 AC: 2 AN: 240418 AF XY: 0.0000152

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000956

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000480 AC: 7 AN: 1458652 Hom.: 0 Cov.: 33 AF XY: 0.00000276 AC XY: 2 AN XY: 725292

African (AFR) AF: 0.00 AC: 0 AN: 33418

American (AMR) AF: 0.00 AC: 0 AN: 44606

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25942

East Asian (EAS) AF: 0.00 AC: 0 AN: 39632

South Asian (SAS) AF: 0.00 AC: 0 AN: 86082

European-Finnish (FIN) AF: 0.0000949 AC: 5 AN: 52712

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1110278

Other (OTH) AF: 0.00 AC: 0 AN: 60222

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Metachromatic leukodystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.67
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.38	T
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D
M_CAP	Uncertain	0.23	D
MetaRNN	Uncertain	0.68	D
MetaSVM	Pathogenic	0.84	D
PhyloP100		5.9
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-3.8	D
REVEL	Pathogenic	0.67
Sift	Uncertain	0.015	D
Sift4G	Uncertain	0.028	D
Vest4		0.52
MVP		0.98
ClinPred		0.97	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.91
Mutation Taster		=44/56	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs199476365; hg19: chr22-51065599;