chr22-50626920-C-G

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1 PM2 PP2

The NM_000487.6(ARSA):​c.598G>C​(p.Glu200Gln) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E200K) has been classified as Benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ARSA NM_000487.6 missense
• Clinical Significance: Not reported in ClinVar
• 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 5 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.

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.598G>C	p.Glu200Gln	missense	Exon 3 of 8	NP_000478.3
	ARSA	NM_001085425.3		c.598G>C	p.Glu200Gln	missense	Exon 4 of 9	NP_001078894.2
	ARSA	NM_001085426.3		c.598G>C	p.Glu200Gln	missense	Exon 4 of 9	NP_001078895.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARSA	ENST00000216124.10	TSL:1 MANE Select	c.598G>C	p.Glu200Gln	missense	Exon 3 of 8	ENSP00000216124.5
	ARSA	ENST00000356098.9	TSL:1	c.598G>C	p.Glu200Gln	missense	Exon 4 of 9	ENSP00000348406.5
	ARSA	ENST00000395619.3	TSL:5	c.598G>C	p.Glu200Gln	missense	Exon 4 of 9	ENSP00000378981.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.28	T
Eigen	Benign	0.16
Eigen_PC	Benign	0.17
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.82	T
M_CAP	Pathogenic	0.50	D
MetaRNN	Uncertain	0.47	T
MetaSVM	Pathogenic	0.99	D
PhyloP100		4.6
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-0.93	N
REVEL	Uncertain	0.52
Sift	Benign	0.37	T
Sift4G	Benign	0.27	T
Vest4		0.20
MVP		0.86
ClinPred		0.79	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.85
Mutation Taster		=59/41	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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;