22-50626920-C-T

Variant names:

• chr22-50626920-C-T
• rs776156197
• NM_000487.6:c.598G>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 6P and 2B. PM1 PM2 PP2 PP3 BP6_Moderate

The NM_000487.6(ARSA):​c.598G>A​(p.Glu200Lys) 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 Benign (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: ARSA NM_000487.6 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 4.58
• 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 4 ACMG points.

• PM1: In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 15 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, 0.838
• BP6: Variant 22-50626920-C-T is Benign according to our data. Variant chr22-50626920-C-T is described in ClinVar as Benign. ClinVar VariationId is 431087.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARSA	NM_000487.6	c.598G>A	p.Glu200Lys	missense_variant	Exon 3 of 8	ENST00000216124.10	NP_000478.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARSA	ENST00000216124.10	c.598G>A	p.Glu200Lys	missense_variant	Exon 3 of 8	1	NM_000487.6	ENSP00000216124.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Metachromatic leukodystrophy Benign:1

May 01, 2017

Neurometabolisches Labor, University hospital Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.69
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.16
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.30	T;T;T;.;T
Eigen	Uncertain	0.22
Eigen_PC	Benign	0.20
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.88	.;.;.;D;D
M_CAP	Pathogenic	0.48	D
MetaRNN	Pathogenic	0.84	D;D;D;D;D
MetaSVM	Pathogenic	0.98	D
PhyloP100		4.6
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-1.3	N;N;N;N;N
REVEL	Uncertain	0.61
Sift	Benign	0.54	T;T;T;T;T
Sift4G	Benign	0.34	T;T;T;T;T
Vest4		0.63
MVP		0.94
ClinPred		0.70	D
GERP RS		5.4
gMVP		0.91
Mutation Taster		=59/41	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs776156197; hg19: chr22-51065348;