rs786200965

Variant names:

• chr22-50627257-TTGCCG-CCCAAGGTT
• rs786200965
• NM_000487.6:c.369_374delCGGCAAinsAACCTTGGG

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1 PM2 PM4_Supporting PP2 PP3 PP5

The NM_000487.6(ARSA):​c.369_374delCGGCAAinsAACCTTGGG​(p.Gly124_Lys125delinsThrLeuGly) variant causes a missense, disruptive inframe insertion change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A123A) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ARSA NM_000487.6 missense, disruptive_inframe_insertion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 7.77
• 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: ClinGen, Myriad Women's Health
• metachromatic leukodystrophy, juvenile form

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp, Ambry Genetics

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PM1: In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 uncertain in NM_000487.6
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_000487.6. Strenght limited to Supporting due to length of the change: 1aa.
• 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: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• PP5: Variant 22-50627257-TTGCCG-CCCAAGGTT is Pathogenic according to our data. Variant chr22-50627257-TTGCCG-CCCAAGGTT is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 166692.

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.369_374delCGGCAAinsAACCTTGGG	p.Gly124_Lys125delinsThrLeuGly	missense disruptive_inframe_insertion	N/A	NP_000478.3
	ARSA	NM_001085425.3		c.369_374delCGGCAAinsAACCTTGGG	p.Gly124_Lys125delinsThrLeuGly	missense disruptive_inframe_insertion	N/A	NP_001078894.2	A0A0C4DFZ2
	ARSA	NM_001085426.3		c.369_374delCGGCAAinsAACCTTGGG	p.Gly124_Lys125delinsThrLeuGly	missense disruptive_inframe_insertion	N/A	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.369_374delCGGCAAinsAACCTTGGG	p.Gly124_Lys125delinsThrLeuGly	missense disruptive_inframe_insertion	N/A	ENSP00000216124.5	A0A0C4DFZ2
	ARSA	ENST00000356098.9	TSL:1	c.369_374delCGGCAAinsAACCTTGGG	p.Gly124_Lys125delinsThrLeuGly	missense disruptive_inframe_insertion	N/A	ENSP00000348406.5	A0A0C4DFZ2
	ARSA	ENST00000395619.3	TSL:5	c.369_374delCGGCAAinsAACCTTGGG	p.Gly124_Lys125delinsThrLeuGly	missense disruptive_inframe_insertion	N/A	ENSP00000378981.3	A0A0C4DFZ2

Frequencies

GnomAD3 genomes Cov.: 33

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

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.8

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs786200965;

hg19: chr22-51065685;