Genetic Variant ARSA:p.Ala470LeufsTer99 (chr22-50625256-GGTCACAGCTGC-G) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PVS1_StrongPP5_Moderate

The NM_000487.6(ARSA):c.1408_1418delGCAGCTGTGAC(p.Ala470LeufsTer99) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. A470A) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Consequence

ARSA
NM_000487.6 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, single submitter P:2O:1

Conservation

PhyloP100: 6.86

Publications

3 publications found

Variant links:

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

ARSA links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 10 pathogenic variants in the truncated region.

PP5

Variant 22-50625256-GGTCACAGCTGC-G is Pathogenic according to our data. Variant chr22-50625256-GGTCACAGCTGC-G is described in ClinVar as Pathogenic. ClinVar VariationId is 198735.Status of the report is criteria_provided_single_submitter, 1 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ARSA	NM_000487.6	MANE Select	c.1408_1418delGCAGCTGTGAC	p.Ala470LeufsTer99	frameshift	Exon 8 of 8	NP_000478.3
ARSA	NM_001085425.3		c.1408_1418delGCAGCTGTGAC	p.Ala470LeufsTer99	frameshift	Exon 9 of 9	NP_001078894.2
ARSA	NM_001085426.3		c.1408_1418delGCAGCTGTGAC	p.Ala470LeufsTer99	frameshift	Exon 9 of 9	NP_001078895.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ARSA	ENST00000216124.10	TSL:1 MANE Select	c.1408_1418delGCAGCTGTGAC	p.Ala470LeufsTer99	frameshift	Exon 8 of 8	ENSP00000216124.5
ARSA	ENST00000356098.9	TSL:1	c.1408_1418delGCAGCTGTGAC	p.Ala470LeufsTer79	frameshift	Exon 9 of 9	ENSP00000348406.5
ARSA	ENST00000395619.3	TSL:5	c.1408_1418delGCAGCTGTGAC	p.Ala470LeufsTer74	frameshift	Exon 9 of 9	ENSP00000378981.3

Frequencies

GnomAD3 genomes

Cov.:

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions as Germline

Significance:Pathogenic

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Metachromatic leukodystrophy, late infantile form (1)

not provided (1)

Metachromatic leukodystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

6.9

Mutation Taster

=0/200

disease causing (ClinVar)

(source)

Splicing

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over