22-50627645-G-T

Variant names:

• chr22-50627645-G-T
• rs375493957
• NM_000487.6:c.135C>A

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 11P and 1B. PS1 PM1 PM2 PM5 PP2 BP4

The NM_000487.6(ARSA):​c.135C>A​(p.Ser45Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000022 in 1,408,000 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S45G) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000022 (0 hom.)
• Consequence: ARSA NM_000487.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• Conservation: PhyloP100: -0.100
• Publications: 1 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 10 ACMG points.

• PS1: Transcript NM_000487.6 (ARSA) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 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 chr22-50627647-T-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 2990837.Status of the report is criteria_provided_single_submitter, 1 stars.
• 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=0.29022777).

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.135C>A	p.Ser45Arg	missense	Exon 1 of 8	NP_000478.3
	ARSA	NM_001085425.3		c.135C>A	p.Ser45Arg	missense	Exon 2 of 9	NP_001078894.2	A0A0C4DFZ2
	ARSA	NM_001085426.3		c.135C>A	p.Ser45Arg	missense	Exon 2 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.135C>A	p.Ser45Arg	missense	Exon 1 of 8	ENSP00000216124.5	A0A0C4DFZ2
	ARSA	ENST00000356098.9	TSL:1	c.135C>A	p.Ser45Arg	missense	Exon 2 of 9	ENSP00000348406.5	A0A0C4DFZ2
	ARSA	ENST00000395619.3	TSL:5	c.135C>A	p.Ser45Arg	missense	Exon 2 of 9	ENSP00000378981.3	A0A0C4DFZ2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000120 AC: 2 AN: 166846 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: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000301

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000220 AC: 31 AN: 1408000 Hom.: 0 Cov.: 33 AF XY: 0.0000201 AC XY: 14 AN XY: 695370

African (AFR) AF: 0.00 AC: 0 AN: 32280

American (AMR) AF: 0.00 AC: 0 AN: 36684

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25270

East Asian (EAS) AF: 0.00 AC: 0 AN: 36788

South Asian (SAS) AF: 0.00 AC: 0 AN: 80118

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49138

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5694

European-Non Finnish (NFE) AF: 0.0000286 AC: 31 AN: 1083662

Other (OTH) AF: 0.00 AC: 0 AN: 58366

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000881 Hom.: 0

Bravo AF: 0.0000151

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000234 AC: 2

ExAC AF: 0.00000856 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	3	-	Metachromatic leukodystrophy (3)
-	1	-	not provided (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.71
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Benign	15
DANN	Uncertain	0.99
DEOGEN2	Benign	0.35	T
Eigen	Benign	-0.77
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.25	N
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.52	D
MetaRNN	Benign	0.29	T
MetaSVM	Pathogenic	1.0	D
PhyloP100		-0.10
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-2.6	D
REVEL	Uncertain	0.63
Sift	Uncertain	0.0090	D
Sift4G	Uncertain	0.0060	D
Vest4		0.78
MVP		0.55
ClinPred		0.59	D
GERP RS		-10
gMVP		0.87
Mutation Taster		=9/91	disease causing

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: rs375493957; hg19: chr22-51066073;