chr22-50627645-G-C

Variant names:

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

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 9P and 1B. PM1 PM2 PM5 PP2 PP5_Moderate BP4

The NM_000487.6(ARSA):​c.135C>G​(p.Ser45Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance 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)
• Consequence: ARSA NM_000487.6 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: -0.100
• Publications: 0 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• 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.
• PP5: Variant 22-50627645-G-C is Pathogenic according to our data. Variant chr22-50627645-G-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 2847035.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.30567676). . Strength limited to SUPPORTING due to the PP5.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARSA	NM_000487.6	MANE Select	c.135C>G	p.Ser45Arg	missense	Exon 1 of 8	NP_000478.3
	ARSA	NM_001085425.3		c.135C>G	p.Ser45Arg	missense	Exon 2 of 9	NP_001078894.2
	ARSA	NM_001085426.3		c.135C>G	p.Ser45Arg	missense	Exon 2 of 9	NP_001078895.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARSA	ENST00000216124.10	TSL:1 MANE Select	c.135C>G	p.Ser45Arg	missense	Exon 1 of 8	ENSP00000216124.5
	ARSA	ENST00000356098.9	TSL:1	c.135C>G	p.Ser45Arg	missense	Exon 2 of 9	ENSP00000348406.5
	ARSA	ENST00000395619.3	TSL:5	c.135C>G	p.Ser45Arg	missense	Exon 2 of 9	ENSP00000378981.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

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	0.71
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Benign	0.35	T
Eigen	Benign	-0.77
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.12	N
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.52	D
MetaRNN	Benign	0.31	T
MetaSVM	Pathogenic	1.0	D
PhyloP100		-0.10
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-2.6	D
REVEL	Uncertain	0.64
Sift	Uncertain	0.0090	D
Sift4G	Uncertain	0.0060	D
Vest4		0.78
MVP		0.55
ClinPred		0.81	D
GERP RS		-10
gMVP		0.87
Mutation Taster		=9/91	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

Other links and lift over

dbSNP: rs375493957; hg19: chr22-51066073;