rs794727704

chr22-50626232-G-Achr22-50626232-G-C

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP3_Strong PP5

The NM_000487.6(ARSA):c.901C>T(p.Arg301Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,042 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R301G) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: ARSA NM_000487.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 3.05

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]

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PM1: In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_000487.6
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr22-50626232-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 197680.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1}.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.967
• PP5: Variant 22-50626232-G-A is Pathogenic according to our data. Variant chr22-50626232-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1048519.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=2}. Variant chr22-50626232-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARSA	NM_000487.6	c.901C>T	p.Arg301Trp	missense_variant	5/8	ENST00000216124.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARSA	ENST00000216124.10	c.901C>T	p.Arg301Trp	missense_variant	5/8	1	NM_000487.6	P1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD3 exomes AF: 0.00000805 AC: 2 AN: 248332 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 134714

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000893

Gnomad OTH exome AF: 0.000166

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461042 Hom.: 0 Cov.: 35 AF XY: 0.00000413 AC XY: 3 AN XY: 726782

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.0000189

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Metachromatic leukodystrophy Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 18, 2023	Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ARSA protein function. For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg301 amino acid residue in ARSA. Other variant(s) that disrupt this residue have been observed in individuals with ARSA-related conditions (PMID: 30674982, 33335837), which suggests that this may be a clinically significant amino acid residue. ClinVar contains an entry for this variant (Variation ID: 1048519). This variant is also known as R299W. This missense change has been observed in individual(s) with metachromatic leukodystrophy (PMID: 12809637, 26462614, 30674982). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 301 of the ARSA protein (p.Arg301Trp). -
Pathogenic, criteria provided, single submitter	clinical testing	Centre for Inherited Metabolic Diseases, Karolinska University Hospital	Mar 25, 2021	- -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 05, 2021

The c.901C>T (p.R301W) alteration is located in exon 5 (coding exon 5) of the ARSA gene. This alteration results from a C to T substitution at nucleotide position 901, causing the arginine (R) at amino acid position 301 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
Cadd	Uncertain	24
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.44	T;T;T;.;T
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Uncertain	0.93	D
M_CAP	Pathogenic	0.73	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	0.99	D;D;D;D;D;D;D
PrimateAI	Uncertain	0.54	T
PROVEAN	Pathogenic	-6.3	D;D;D;D;D
REVEL	Pathogenic	0.79
Sift	Uncertain	0.0010	D;D;D;D;D
Sift4G	Uncertain	0.0020	D;D;D;D;D
Vest4		0.85
MVP		0.99
ClinPred		0.99	D
GERP RS		3.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.94

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs794727704; hg19: chr22-51064660;