Variant X-2909866-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2

The NM_001669.4(ARSD):c.1249G>A(p.Val417Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000579 in 1,208,182 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 27 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000045 ( 0 hom., 0 hem., cov: 21)

Exomes 𝑓: 0.000059 ( 0 hom. 27 hem. )

Consequence

ARSD
NM_001669.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.02

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 Likely_benign. Variant got -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.3589223).

BS2

High Hemizygotes in GnomAdExome4 at 27 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARSD	NM_001669.4 link	c.1249G>A	p.Val417Met	missense_variant	Exon 8 of 10	ENST00000381154.6	NP_001660.2	P51689-1A0A140VK06
ARSD	XM_005274514.3 link	c.1114G>A	p.Val372Met	missense_variant	Exon 7 of 9		XP_005274571.1
ARSD	XM_047442108.1 link	c.1111G>A	p.Val371Met	missense_variant	Exon 8 of 10		XP_047298064.1
ARSD	XM_005274515.3 link	c.1249G>A	p.Val417Met	missense_variant	Exon 8 of 10		XP_005274572.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ARSD	ENST00000381154.6 link	c.1249G>A	p.Val417Met	missense_variant	Exon 8 of 10	1	NM_001669.4	ENSP00000370546.1	P51689-1
ARSD	ENST00000458014.1 link	c.55G>A	p.Val19Met	missense_variant	Exon 1 of 4	3		ENSP00000409180.1	H7C327
ARSD	ENST00000495294.1 link	n.119-1061G>A		intron_variant	Intron 1 of 2	2

Frequencies

GnomAD3 genomes

AF:

0.0000454

AC:

AN:

110252

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

32466

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:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000947

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000274

AC:

AN:

182428

Hom.:

AF XY:

0.0000597

AC XY:

AN XY:

66966

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000614

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000592

AC:

AN:

1097890

Hom.:

Cov.:

AF XY:

0.0000743

AC XY:

AN XY:

363264

show subpopulations

Gnomad4 AFR exome

AF:

0.0000379

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000185

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000713

Gnomad4 OTH exome

AF:

0.0000434

GnomAD4 genome

AF:

0.0000453

AC:

AN:

110292

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

32516

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000947

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000340

ExAC

AF:

0.0000576

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 06, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1249G>A (p.V417M) alteration is located in exon 8 (coding exon 8) of the ARSD gene. This alteration results from a G to A substitution at nucleotide position 1249, causing the valine (V) at amino acid position 417 to be replaced by a methionine (M). 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

0.22

BayesDel_addAF

Benign

-0.081

BayesDel_noAF

Benign

-0.17

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.65

D;.

FATHMM_MKL

Benign

0.24

LIST_S2

Uncertain

0.93

D;D

M_CAP

Pathogenic

0.31

MetaRNN

Benign

0.36

T;T

MetaSVM

Uncertain

0.63

MutationAssessor

Benign

1.4

L;.

PrimateAI

Uncertain

0.53

PROVEAN

Benign

-2.2

N;N

REVEL

Uncertain

0.37

Sift

Uncertain

0.019

D;D

Sift4G

Uncertain

0.018

D;D

Polyphen

0.88

P;.

Vest4

0.44

MVP

0.95

MPC

0.51

ClinPred

0.24

GERP RS

-0.47

Varity_R

0.18

gMVP

0.58

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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