NM_000487.6:c.465G>C

Variant names:

• chr22-50627166-C-G
• rs199476377
• NM_000487.6:c.465G>C

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1 PM2 PP2 PP3_Strong

The NM_000487.6(ARSA):​c.465G>C​(p.Gln155His) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000137 in 1,457,180 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as not provided (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Synonymous variant affecting the same amino acid position (i.e. Q155Q) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ARSA NM_000487.6 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 5.93
• Publications: 6 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 11 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 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: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

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.465G>C	p.Gln155His	missense splice_region	Exon 2 of 8	NP_000478.3
	ARSA	NM_001085425.3		c.465G>C	p.Gln155His	missense splice_region	Exon 3 of 9	NP_001078894.2	A0A0C4DFZ2
	ARSA	NM_001085426.3		c.465G>C	p.Gln155His	missense splice_region	Exon 3 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.465G>C	p.Gln155His	missense splice_region	Exon 2 of 8	ENSP00000216124.5	A0A0C4DFZ2
	ARSA	ENST00000356098.9	TSL:1	c.465G>C	p.Gln155His	missense splice_region	Exon 3 of 9	ENSP00000348406.5	A0A0C4DFZ2
	ARSA	ENST00000395619.3	TSL:5	c.465G>C	p.Gln155His	missense splice_region	Exon 3 of 9	ENSP00000378981.3	A0A0C4DFZ2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000416 AC: 1 AN: 240440 AF XY: 0.00000760

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000941

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1457180 Hom.: 0 Cov.: 33 AF XY: 0.00000276 AC XY: 2 AN XY: 724290

African (AFR) AF: 0.00 AC: 0 AN: 33378

American (AMR) AF: 0.00 AC: 0 AN: 44546

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25906

East Asian (EAS) AF: 0.00 AC: 0 AN: 39592

South Asian (SAS) AF: 0.00 AC: 0 AN: 86084

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52716

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5750

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1109076

Other (OTH) AF: 0.00 AC: 0 AN: 60132

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000825 AC: 1

ClinVar

ClinVar submissions

Significance: not provided

Revision: no classification provided

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.79
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.23
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.33	T
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.87	D
M_CAP	Pathogenic	0.48	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Pathogenic	1.0	D
PhyloP100		5.9
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-1.8	N
REVEL	Pathogenic	0.73
Sift	Benign	0.31	T
Sift4G	Benign	0.33	T
Vest4		0.82
MVP		0.99
ClinPred		0.82	D
GERP RS		4.7
gMVP		0.90
Mutation Taster		=0/100	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.84		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.84		Position offset: 0

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

Other links and lift over

dbSNP: rs199476377; hg19: chr22-51065594;