rs786204673

Variant names:

• chr22-50627326-AG-A
• rs786204673
• NM_000487.6:c.304delC

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000487.6(ARSA):​c.304delC​(p.Leu102CysfsTer6) variant causes a frameshift change. The variant allele was found at a frequency of 0.0000132 in 1,437,858 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. L102L) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: ARSA NM_000487.6 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 3.92
• 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 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 22-50627326-AG-A is Pathogenic according to our data. Variant chr22-50627326-AG-A is described in ClinVar as Pathogenic. ClinVar VariationId is 189073.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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.304delC	p.Leu102CysfsTer6	frameshift	Exon 2 of 8	NP_000478.3
	ARSA	NM_001085425.3		c.304delC	p.Leu102CysfsTer6	frameshift	Exon 3 of 9	NP_001078894.2	A0A0C4DFZ2
	ARSA	NM_001085426.3		c.304delC	p.Leu102CysfsTer6	frameshift	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.304delC	p.Leu102CysfsTer6	frameshift	Exon 2 of 8	ENSP00000216124.5	A0A0C4DFZ2
	ARSA	ENST00000356098.9	TSL:1	c.304delC	p.Leu102CysfsTer6	frameshift	Exon 3 of 9	ENSP00000348406.5	A0A0C4DFZ2
	ARSA	ENST00000395619.3	TSL:5	c.304delC	p.Leu102CysfsTer6	frameshift	Exon 3 of 9	ENSP00000378981.3	A0A0C4DFZ2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.0000132 AC: 19 AN: 1437858 Hom.: 0 Cov.: 33 AF XY: 0.0000126 AC XY: 9 AN XY: 713604

African (AFR) AF: 0.00 AC: 0 AN: 33090

American (AMR) AF: 0.00 AC: 0 AN: 40702

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25638

East Asian (EAS) AF: 0.00 AC: 0 AN: 38698

South Asian (SAS) AF: 0.00 AC: 0 AN: 83628

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49316

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5740

European-Non Finnish (NFE) AF: 0.0000172 AC: 19 AN: 1101562

Other (OTH) AF: 0.00 AC: 0 AN: 59484

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	Metachromatic leukodystrophy (3)
1	-	-	Metachromatic leukodystrophy, late infantile form (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.9
Mutation Taster		=0/200	disease causing (ClinVar)

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: rs786204673; hg19: chr22-51065754;