Genetic Variant NM_000487.6:c.1229C>A (chr22-50625446-G-T) – ACMG Classification: Likely_pathogenic (7 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1PM2PM5PP2

The NM_000487.6(ARSA):c.1229C>A(p.Thr410Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00000138 in 1,448,598 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. T410I) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

ARSA
NM_000487.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.29

Publications

0 publications found

Variant links:

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: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp

ARSA links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 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 chr22-50625446-G-A is described in CliVar as Likely_pathogenic. Clinvar id is 3092.Status of the report is criteria_provided_single_submitter, 1 stars.

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARSA	NM_000487.6 link	c.1229C>A	p.Thr410Asn	missense_variant	Exon 8 of 8	ENST00000216124.10	NP_000478.3	P15289A0A0C4DFZ2B4DVI5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARSA	ENST00000216124.10 link	c.1229C>A	p.Thr410Asn	missense_variant	Exon 8 of 8	1	NM_000487.6	ENSP00000216124.5		A0A0C4DFZ2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000138

AC:

AN:

1448598

Hom.:

Cov.:

AF XY:

0.00000139

AC XY:

AN XY:

718936

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33288

American (AMR)

AF:

0.00

AC:

AN:

44274

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25218

East Asian (EAS)

AF:

0.00

AC:

AN:

39520

South Asian (SAS)

AF:

0.00

AC:

AN:

84808

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51732

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5702

European-Non Finnish (NFE)

AF:

0.00000181

AC:

AN:

1104186

Other (OTH)

AF:

0.00

AC:

AN:

59870

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Uncertain

-0.030

CADD

Uncertain

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.29

T;T;T;.;T

Eigen

Benign

-0.18

Eigen_PC

Benign

-0.0067

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.79

.;.;.;T;T

M_CAP

Benign

0.062

MetaRNN

Uncertain

0.51

D;D;D;D;D

MetaSVM

Benign

-0.81

PhyloP100

6.3

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-1.3

N;N;N;N;N

REVEL

Uncertain

0.43

Sift

Benign

0.17

T;T;T;T;T

Sift4G

Benign

0.35

T;T;T;T;T

Vest4

0.54

MVP

0.91

ClinPred

0.98

GERP RS

4.4

gMVP

0.69

Mutation Taster

=15/85

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.26

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.26

Position offset: -31

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over