NM_000487.6:c.1108-3C>T

Variant names:

• chr22-50625684-G-A
• rs1001100248
• NM_000487.6:c.1108-3C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000487.6(ARSA):​c.1108-3C>T variant causes a splice region, intron 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. 2/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 34)
• Consequence: ARSA NM_000487.6 splice_region, intron
• Scores: Splicing: ADA: 0.002303
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.303
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.4).

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.1108-3C>T		splice_region intron	N/A	NP_000478.3
	ARSA	NM_001085425.3		c.1108-3C>T		splice_region intron	N/A	NP_001078894.2
	ARSA	NM_001085426.3		c.1108-3C>T		splice_region intron	N/A	NP_001078895.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARSA	ENST00000216124.10	TSL:1 MANE Select	c.1108-3C>T		splice_region intron	N/A	ENSP00000216124.5
	ARSA	ENST00000356098.9	TSL:1	c.1108-3C>T		splice_region intron	N/A	ENSP00000348406.5
	ARSA	ENST00000395619.3	TSL:5	c.1108-3C>T		splice_region intron	N/A	ENSP00000378981.3

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 41

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.40
CADD	Benign	14
DANN	Benign	0.84
PhyloP100		0.30

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0023
dbscSNV1_RF	Benign	0.11
SpliceAI score (max)		0.27		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.27		Position offset: -5

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

Other links and lift over

dbSNP: rs1001100248; hg19: chr22-51064112;