22-50626211-A-G

Variant names:

• chr22-50626211-A-G
• rs199476379
• NM_000487.6:c.922T>C

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1 PM2 PP2 PP3_Moderate PP5_Moderate

The NM_000487.6(ARSA):​c.922T>C​(p.Tyr308His) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y308C) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 34)
• Consequence: ARSA NM_000487.6 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2 U:1 O:1
• Conservation: PhyloP100: 6.17
• Publications: 4 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: Likely_pathogenic. The variant received 9 ACMG points.

• PM1: In a hotspot region, there are 25 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 uncertain in NM_000487.6
• PM2: Very rare variant in population databases, with high coverage
• 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: MetaRNN computational evidence supports a deleterious effect, 0.923
• PP5: Variant 22-50626211-A-G is Pathogenic according to our data. Variant chr22-50626211-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 68161.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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARSA	NM_000487.6	MANE Select	c.922T>C	p.Tyr308His	missense	Exon 5 of 8	NP_000478.3
	ARSA	NM_001085425.3		c.922T>C	p.Tyr308His	missense	Exon 6 of 9	NP_001078894.2	A0A0C4DFZ2
	ARSA	NM_001085426.3		c.922T>C	p.Tyr308His	missense	Exon 6 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.922T>C	p.Tyr308His	missense	Exon 5 of 8	ENSP00000216124.5	A0A0C4DFZ2
	ARSA	ENST00000356098.9	TSL:1	c.922T>C	p.Tyr308His	missense	Exon 6 of 9	ENSP00000348406.5	A0A0C4DFZ2
	ARSA	ENST00000395619.3	TSL:5	c.922T>C	p.Tyr308His	missense	Exon 6 of 9	ENSP00000378981.3	A0A0C4DFZ2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 34

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	1	-	Metachromatic leukodystrophy (3)
-	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.53
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.23
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.43	T
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D
M_CAP	Uncertain	0.24	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Pathogenic	0.96	D
PhyloP100		6.2
PrimateAI	Uncertain	0.58	T
PROVEAN	Pathogenic	-4.5	D
REVEL	Pathogenic	0.84
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Vest4		0.82
MVP		0.99
ClinPred		1.0	D
GERP RS		5.4
gMVP		0.90
Mutation Taster		=1/99	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs199476379; hg19: chr22-51064639;