rs199476390

Variant names:

• chr22-50626191-C-A
• rs199476390
• NM_000487.6:c.942G>T

Your query was ambiguous. Multiple possible variants found:

• chr22-50626191-C-A
• chr22-50626191-C-G
• chr22-50626191-C-T

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1 PM2 PP2 PP3 PP5

The NM_000487.6(ARSA):​c.942G>T​(p.Glu314Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000206 in 1,458,154 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 Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Synonymous variant affecting the same amino acid position (i.e. E314E) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: ARSA NM_000487.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:1 O:1
• Conservation: PhyloP100: -0.717
• 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 7 ACMG points.

• PM1: In a hotspot region, there are 18 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in NM_000487.6
• PM2: Very rare variant in population databases, with high coverage
• 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: MetaRNN computational evidence supports a deleterious effect, 0.755
• PP5: Variant 22-50626191-C-A is Pathogenic according to our data. Variant chr22-50626191-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 68166.

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.942G>T	p.Glu314Asp	missense	Exon 5 of 8	NP_000478.3
	ARSA	NM_001085425.3		c.942G>T	p.Glu314Asp	missense	Exon 6 of 9	NP_001078894.2	A0A0C4DFZ2
	ARSA	NM_001085426.3		c.942G>T	p.Glu314Asp	missense	Exon 6 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.942G>T	p.Glu314Asp	missense	Exon 5 of 8	ENSP00000216124.5	A0A0C4DFZ2
	ARSA	ENST00000356098.9	TSL:1	c.942G>T	p.Glu314Asp	missense	Exon 6 of 9	ENSP00000348406.5	A0A0C4DFZ2
	ARSA	ENST00000395619.3	TSL:5	c.942G>T	p.Glu314Asp	missense	Exon 6 of 9	ENSP00000378981.3	A0A0C4DFZ2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD2 exomes AF: 0.0000207 AC: 5 AN: 241008 AF XY: 0.0000306

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: 0.0000461

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000206 AC: 30 AN: 1458154 Hom.: 0 Cov.: 35 AF XY: 0.0000248 AC XY: 18 AN XY: 725078

African (AFR) AF: 0.00 AC: 0 AN: 33450

American (AMR) AF: 0.00 AC: 0 AN: 44046

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25956

East Asian (EAS) AF: 0.00 AC: 0 AN: 39528

South Asian (SAS) AF: 0.00 AC: 0 AN: 85514

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52876

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.0000261 AC: 29 AN: 1110764

Other (OTH) AF: 0.0000166 AC: 1 AN: 60254

GnomAD4 genome Cov.: 34

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
2	1	-	Metachromatic leukodystrophy (3)
1	-	-	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Pathogenic	0.16
CADD	Benign	17
DANN	Uncertain	1.0
DEOGEN2	Benign	0.37	T
Eigen	Benign	0.17
Eigen_PC	Benign	0.071
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Uncertain	0.91	D
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.75	D
MetaSVM	Uncertain	0.63	D
PhyloP100		-0.72
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-2.1	N
REVEL	Pathogenic	0.73
Sift	Benign	0.35	T
Sift4G	Benign	0.48	T
Vest4		0.66
MVP		0.91
ClinPred		0.64	D
GERP RS		0.83
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.97
Mutation Taster		=1/99	disease causing (ClinVar)

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: rs199476390; hg19: chr22-51064619;