Variant X-2908745-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The ENST00000381154.6(ARSD):c.1396G>A(p.Ala466Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000551 in 1,089,538 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 21)

Exomes 𝑓: 0.0000055 ( 0 hom. 1 hem. )

Consequence

ARSD
ENST00000381154.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.32

Variant links:

Genes affected

ARSD (HGNC:717): (arylsulfatase D) The protein encoded by this gene is a member of the sulfatase family. Sulfatases are essential for the correct composition of bone and cartilage matrix. The encoded protein is postranslationally glycosylated and localized to the lysosome. This gene is located within a cluster of similar arylsulfatase genes on chromosome X. A related pseudogene has been identified in the pseudoautosomal region of chromosome Y. [provided by RefSeq, Jul 2011]

ARSD links:

ARSD (HGNC:):

ARSD links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.874

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARSD	NM_001669.4 linkuse as main transcript	c.1396G>A	p.Ala466Thr	missense_variant	9/10	ENST00000381154.6	NP_001660.2	P51689-1A0A140VK06
ARSD	XM_005274514.3 linkuse as main transcript	c.1261G>A	p.Ala421Thr	missense_variant	8/9		XP_005274571.1
ARSD	XM_047442108.1 linkuse as main transcript	c.1258G>A	p.Ala420Thr	missense_variant	9/10		XP_047298064.1
ARSD	XM_005274515.3 linkuse as main transcript	c.1396G>A	p.Ala466Thr	missense_variant	9/10		XP_005274572.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
ARSD	ENST00000381154.6 linkuse as main transcript	c.1396G>A	p.Ala466Thr	missense_variant	9/10	1	NM_001669.4	ENSP00000370546.1	P51689-1
ARSD	ENST00000458014.1 linkuse as main transcript	c.202G>A	p.Ala68Thr	missense_variant	2/4	3		ENSP00000409180.1	H7C327
ARSD	ENST00000495294.1 linkuse as main transcript	n.179G>A		non_coding_transcript_exon_variant	2/3	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000551

AC:

AN:

1089538

Hom.:

Cov.:

AF XY:

0.00000281

AC XY:

AN XY:

356398

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000292

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000334

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000248

Gnomad4 NFE exome

AF:

0.00000239

Gnomad4 OTH exome

AF:

0.0000219

GnomAD4 genome

Cov.:

Bravo

AF:

0.0000416

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 20, 2023

The c.1396G>A (p.A466T) alteration is located in exon 9 (coding exon 9) of the ARSD gene. This alteration results from a G to A substitution at nucleotide position 1396, causing the alanine (A) at amino acid position 466 to be replaced by a threonine (T). 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

AlphaMissense

Benign

0.23

BayesDel_addAF

Pathogenic

0.19

BayesDel_noAF

Uncertain

0.030

CADD

Benign

DANN

Benign

0.88

DEOGEN2

Uncertain

0.69

D;.

FATHMM_MKL

Benign

0.68

LIST_S2

Benign

0.84

T;T

M_CAP

Pathogenic

0.29

MetaRNN

Pathogenic

0.87

D;D

MetaSVM

Uncertain

0.67

MutationAssessor

Benign

2.0

M;.

MutationTaster

Benign

1.0

PrimateAI

Pathogenic

0.82

PROVEAN

Uncertain

-3.2

D;D

REVEL

Uncertain

0.57

Sift

Benign

0.096

T;T

Sift4G

Benign

0.10

T;T

Polyphen

0.66

P;.

Vest4

0.54

MutPred

0.69

Loss of MoRF binding (P = 0.1288);.;

MVP

0.91

MPC

0.28

ClinPred

0.80

GERP RS

2.4

Varity_R

0.31

gMVP

0.83

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over