22-50625401-T-G

Variant names:

• chr22-50625401-T-G
• NM_000487.6:c.1274A>C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP3_Moderate

The NM_000487.6(ARSA):​c.1274A>C​(p.His425Pro) 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. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ARSA NM_000487.6 missense
• Clinical Significance: Not reported in ClinVar
• 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 Likely_pathogenic. Variant got 6 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
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.929

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARSA	NM_000487.6	c.1274A>C	p.His425Pro	missense_variant	Exon 8 of 8	ENST00000216124.10	NP_000478.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARSA	ENST00000216124.10	c.1274A>C	p.His425Pro	missense_variant	Exon 8 of 8	1	NM_000487.6	ENSP00000216124.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1446752 Hom.: 0 Cov.: 32 AF XY: 0.00000139 AC XY: 1 AN XY: 717480

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000181

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
CADD	Uncertain	26
DANN	Uncertain	0.98
DEOGEN2	Benign	0.38	T;T;T;.;T
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.77	.;.;.;T;T
M_CAP	Uncertain	0.26	D
MetaRNN	Pathogenic	0.93	D;D;D;D;D
MetaSVM	Uncertain	0.75	D
PrimateAI	Uncertain	0.52	T
PROVEAN	Pathogenic	-8.7	D;D;D;D;D
REVEL	Pathogenic	0.77
Sift	Uncertain	0.0040	D;D;D;D;D
Sift4G	Uncertain	0.0050	D;D;D;D;D
Vest4		0.63
MVP		0.95
ClinPred		1.0	D
GERP RS		5.6
gMVP		0.92

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr22-51063829;