rs786204748

Variant names:

• chr22-50625443-GTGGTATCAC-G
• rs765905826
• NM_000487.6:c.1223_1231delGTGATACCA

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM1 PM2 PM4 PP5_Very_Strong

The ENST00000216124.10(ARSA):​c.1223_1231delGTGATACCA​(p.Ser408_Thr410del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.00000276 in 1,447,764 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: ARSA ENST00000216124.10 disruptive_inframe_deletion
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 6.29
• 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp

ACMG classification

Our verdict: Pathogenic. The variant received 14 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in ENST00000216124.10
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in ENST00000216124.10.
• PP5: Variant 22-50625443-GTGGTATCAC-G is Pathogenic according to our data. Variant chr22-50625443-GTGGTATCAC-G is described in ClinVar as Pathogenic. ClinVar VariationId is 189170.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000216124.10. 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.1223_1231delGTGATACCA	p.Ser408_Thr410del	disruptive_inframe_deletion	Exon 8 of 8	NP_000478.3
	ARSA	NM_001085425.3		c.1223_1231delGTGATACCA	p.Ser408_Thr410del	disruptive_inframe_deletion	Exon 9 of 9	NP_001078894.2
	ARSA	NM_001085426.3		c.1223_1231delGTGATACCA	p.Ser408_Thr410del	disruptive_inframe_deletion	Exon 9 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.1223_1231delGTGATACCA	p.Ser408_Thr410del	disruptive_inframe_deletion	Exon 8 of 8	ENSP00000216124.5
	ARSA	ENST00000356098.9	TSL:1	c.1223_1231delGTGATACCA	p.Ser408_Thr410del	disruptive_inframe_deletion	Exon 9 of 9	ENSP00000348406.5
	ARSA	ENST00000395619.3	TSL:5	c.1223_1231delGTGATACCA	p.Ser408_Thr410del	disruptive_inframe_deletion	Exon 9 of 9	ENSP00000378981.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000837 AC: 2 AN: 238866 AF XY: 0.0000154

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: 0.00000935

Gnomad OTH exome AF: 0.000171

GnomAD4 exome AF: 0.00000276 AC: 4 AN: 1447764 Hom.: 0 AF XY: 0.00000418 AC XY: 3 AN XY: 718444

African (AFR) AF: 0.00 AC: 0 AN: 33270

American (AMR) AF: 0.0000226 AC: 1 AN: 44232

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25150

East Asian (EAS) AF: 0.00 AC: 0 AN: 39506

South Asian (SAS) AF: 0.00 AC: 0 AN: 84778

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51710

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5706

European-Non Finnish (NFE) AF: 0.00000272 AC: 3 AN: 1103598

Other (OTH) AF: 0.00 AC: 0 AN: 59814

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
4	-	-	Metachromatic leukodystrophy (4)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		6.3
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs765905826; hg19: chr22-51063871;