X-2907437-G-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_001669.4(ARSD):c.1616C>A(p.Ala539Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000661 in 1,210,336 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 31 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000071 ( 0 hom., 4 hem., cov: 24)

Exomes 𝑓: 0.000066 ( 0 hom. 27 hem. )

Consequence

ARSD
NM_001669.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1B:1

Conservation

PhyloP100: 2.30

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.016805112).

BS2

High Hemizygotes in GnomAd4 at 4 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARSD	NM_001669.4 link	c.1616C>A	p.Ala539Asp	missense_variant	Exon 10 of 10	ENST00000381154.6	NP_001660.2	P51689-1A0A140VK06
ARSD	XM_005274514.3 link	c.1481C>A	p.Ala494Asp	missense_variant	Exon 9 of 9		XP_005274571.1
ARSD	XM_047442108.1 link	c.1478C>A	p.Ala493Asp	missense_variant	Exon 10 of 10		XP_047298064.1
ARSD	XM_005274515.3 link	c.*540C>A		3_prime_UTR_variant	Exon 10 of 10		XP_005274572.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ARSD	ENST00000381154.6 link	c.1616C>A	p.Ala539Asp	missense_variant	Exon 10 of 10	1	NM_001669.4	ENSP00000370546.1	P51689-1
ARSD	ENST00000458014.1 link	c.422C>A	p.Ala141Asp	missense_variant	Exon 3 of 4	3		ENSP00000409180.1	H7C327
ARSD	ENST00000495294.1 link	n.751C>A		non_coding_transcript_exon_variant	Exon 3 of 3	2

Frequencies

GnomAD3 genomes

AF:

0.0000710

AC:

AN:

112669

Hom.:

Cov.:

AF XY:

0.000115

AC XY:

AN XY:

34807

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00197

Gnomad SAS

AF:

0.000367

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000145

AC:

AN:

179507

Hom.:

AF XY:

0.000155

AC XY:

AN XY:

64631

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00182

Gnomad SAS exome

AF:

0.0000537

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000656

AC:

AN:

1097614

Hom.:

Cov.:

AF XY:

0.0000744

AC XY:

AN XY:

362998

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00152

Gnomad4 SAS exome

AF:

0.000352

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000119

Gnomad4 OTH exome

AF:

0.000130

GnomAD4 genome

AF:

0.0000710

AC:

AN:

112722

Hom.:

Cov.:

AF XY:

0.000115

AC XY:

AN XY:

34870

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00197

Gnomad4 SAS

AF:

0.000368

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000142

Hom.:

Bravo

AF:

0.000117

ExAC

AF:

0.000157

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 14, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1616C>A (p.A539D) alteration is located in exon 10 (coding exon 10) of the ARSD gene. This alteration results from a C to A substitution at nucleotide position 1616, causing the alanine (A) at amino acid position 539 to be replaced by an aspartic acid (D). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

ARSD-related disorder

Benign:1

Mar 01, 2022

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.086

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.32

CADD

Benign

DANN

Benign

0.79

DEOGEN2

Uncertain

0.67

D;.

FATHMM_MKL

Benign

0.039

LIST_S2

Benign

0.11

T;T

M_CAP

Uncertain

0.087

MetaRNN

Benign

0.017

T;T

MetaSVM

Benign

-0.39

MutationAssessor

Benign

1.6

L;.

PrimateAI

Uncertain

0.59

PROVEAN

Uncertain

-2.5

N;D

REVEL

Benign

0.17

Sift

Benign

0.47

T;T

Sift4G

Benign

0.47

T;T

Polyphen

0.40

B;.

Vest4

0.12

MutPred

0.40

Gain of catalytic residue at A539 (P = 0.0585);.;

MVP

0.96

MPC

0.26

ClinPred

0.072

GERP RS

0.086

Varity_R

0.34

gMVP

0.58

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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