rs1135401757

Positions:

• chr22-50625401-T-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM2 PP5_Very_Strong

The NM_000487.6(ARSA):​c.1274A>G​(p.His425Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000138 in 1,446,752 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ARSA NM_000487.6 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 5.67

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 12 ACMG points.

• PM1: In a strand (size 9) in uniprot entity ARSA_HUMAN there are 10 pathogenic changes around while only 0 benign (100%) in NM_000487.6
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 22-50625401-T-C is Pathogenic according to our data. Variant chr22-50625401-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 431090.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARSA	NM_000487.6	c.1274A>G	p.His425Arg	missense_variant	8/8	ENST00000216124.10	NP_000478.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARSA	ENST00000216124.10	c.1274A>G	p.His425Arg	missense_variant	8/8	1	NM_000487.6	ENSP00000216124	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1446752 Hom.: 0 Cov.: 32 AF XY: 0.00000279 AC XY: 2 AN XY: 717480

Gnomad4 AFR exome AF: 0.0000301

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.07e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Metachromatic leukodystrophy Pathogenic:2

Pathogenic, criteria provided, single submitter	research	Neurometabolisches Labor, University hospital Tuebingen	May 01, 2017	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 30, 2024	Variant summary: ARSA c.1274A>G (p.His425Arg) results in a non-conservative amino acid change in the encoded protein sequence. Four of four in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 241050 control chromosomes (gnomAD). c.1274A>G has been reported in the literature in an individual affected with Metachromatic Leukodystrophy (Bohringer_2017). These data do not allow any conclusion about variant significance. This publication also reports experimental evidence evaluating an impact on protein function, finding that the variant results in <10% of normal activity. The following publication has been ascertained in the context of this evaluation (PMID: 28762252). ClinVar contains an entry for this variant (Variation ID: 431090). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.23
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.38	T;T;T;.;T
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.81	.;.;.;T;T
M_CAP	Uncertain	0.16	D
MetaRNN	Uncertain	0.61	D;D;D;D;D
MetaSVM	Uncertain	0.75	D
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Uncertain	0.58	T
PROVEAN	Pathogenic	-7.0	D;D;D;D;D
REVEL	Pathogenic	0.75
Sift	Uncertain	0.0040	D;D;D;D;D
Sift4G	Uncertain	0.021	D;D;D;D;D
Vest4		0.32
MVP		0.98
ClinPred		1.0	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.85

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs1135401757; hg19: chr22-51063829; COSMIC: COSV99332265; COSMIC: COSV99332265;