22-50625633-G-T

Variant names:

• chr22-50625633-G-T
• NM_000487.6:c.1156C>A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PM5

The NM_000487.6(ARSA):​c.1156C>A​(p.Arg386Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 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. R386C) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 34)
• Consequence: ARSA NM_000487.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.27

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr22-50625633-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARSA	NM_000487.6	c.1156C>A	p.Arg386Ser	missense_variant	Exon 7 of 8	ENST00000216124.10	NP_000478.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARSA	ENST00000216124.10	c.1156C>A	p.Arg386Ser	missense_variant	Exon 7 of 8	1	NM_000487.6	ENSP00000216124.5

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 46

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.010
CADD	Benign	23
DANN	Uncertain	0.97
DEOGEN2	Benign	0.26	T;T;T;.;T
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.41
FATHMM_MKL	Benign	0.43	N
LIST_S2	Benign	0.82	.;.;.;T;T
M_CAP	Benign	0.066	D
MetaRNN	Benign	0.18	T;T;T;T;T
MetaSVM	Uncertain	-0.27	T
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.79	N;N;N;N;N
REVEL	Uncertain	0.46
Sift	Benign	0.39	T;T;T;T;T
Sift4G	Benign	0.40	T;T;T;T;T
Vest4		0.22
MVP		0.71
ClinPred		0.50	D
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.69

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.34		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.34		Position offset: 4

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: chr22-51064061;