Genetic Variant NM_001669.4:c.1498G>A (chrX-2907555-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001669.4(ARSD):c.1498G>A(p.Val500Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00202 in 1,155,856 control chromosomes in the GnomAD database, including 30 homozygotes. There are 642 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0093 ( 14 hom., 286 hem., cov: 24)

Exomes 𝑓: 0.0012 ( 16 hom. 356 hem. )

Consequence

ARSD
NM_001669.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -2.70

Publications

4 publications found

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 was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.005255133).

BP6

Variant X-2907555-C-T is Benign according to our data. Variant chrX-2907555-C-T is described in ClinVar as Benign. ClinVar VariationId is 787152.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00934 (1055/112968) while in subpopulation AFR AF = 0.0307 (957/31191). AF 95% confidence interval is 0.0291. There are 14 homozygotes in GnomAd4. There are 286 alleles in the male GnomAd4 subpopulation. Median coverage is 24. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 14 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001669.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARSD	NM_001669.4	MANE Select	c.1498G>A	p.Val500Ile	missense	Exon 10 of 10	NP_001660.2	P51689-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ARSD	ENST00000381154.6	TSL:1 MANE Select	c.1498G>A	p.Val500Ile	missense	Exon 10 of 10	ENSP00000370546.1	P51689-1
ARSD	ENST00000954947.1		c.1363G>A	p.Val455Ile	missense	Exon 9 of 9	ENSP00000625006.1
ARSD	ENST00000954948.1		c.1063G>A	p.Val355Ile	missense	Exon 7 of 7	ENSP00000625007.1

Frequencies

GnomAD3 genomes

AF:

0.00931

AC:

1051

AN:

112921

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0306

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00631

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000725

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00417

Gnomad NFE

AF:

0.000225

Gnomad OTH

AF:

0.00988

GnomAD2 exomes

AF:

0.00326

AC:

359

AN:

109976

AF XY:

0.00254

show subpopulations

Gnomad AFR exome

AF:

0.0321

Gnomad AMR exome

AF:

0.00182

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000173

Gnomad OTH exome

AF:

0.00277

GnomAD4 exome

AF:

0.00123

AC:

1278

AN:

1042888

Hom.:

Cov.:

AF XY:

0.00109

AC XY:

356

AN XY:

327542

show subpopulations

African (AFR)

AF:

0.0326

AC:

822

AN:

25202

American (AMR)

AF:

0.00222

AC:

AN:

27468

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

16733

East Asian (EAS)

AF:

0.00

AC:

AN:

28587

South Asian (SAS)

AF:

0.00202

AC:

AN:

45941

European-Finnish (FIN)

AF:

0.00

AC:

AN:

37819

Middle Eastern (MID)

AF:

0.00204

AC:

AN:

3917

European-Non Finnish (NFE)

AF:

0.000215

AC:

175

AN:

813536

Other (OTH)

AF:

0.00272

AC:

119

AN:

43685

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

109

164

218

273

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

128

160

<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

AF:

0.00934

AC:

1055

AN:

112968

Hom.:

Cov.:

AF XY:

0.00815

AC XY:

286

AN XY:

35112

show subpopulations

African (AFR)

AF:

0.0307

AC:

957

AN:

31191

American (AMR)

AF:

0.00631

AC:

AN:

10783

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2660

East Asian (EAS)

AF:

0.00

AC:

AN:

3574

South Asian (SAS)

AF:

0.000727

AC:

AN:

2751

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6258

Middle Eastern (MID)

AF:

0.00457

AC:

AN:

219

European-Non Finnish (NFE)

AF:

0.000225

AC:

AN:

53308

Other (OTH)

AF:

0.00977

AC:

AN:

1536

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

124

165

206

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00323

Hom.:

Bravo

AF:

0.0108

ESP6500AA

AF:

0.0278

AC:

106

ESP6500EA

AF:

0.000149

AC:

ExAC

AF:

0.00261

AC:

306

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.065

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.70

CADD

Benign

0.0010

(source)

DANN

Benign

0.75

DEOGEN2

Benign

0.33

FATHMM_MKL

Benign

0.0029

LIST_S2

Benign

0.087

MetaRNN

Benign

0.0053

MetaSVM

Benign

-0.81

MutationAssessor

Benign

0.83

PhyloP100

-2.7

PrimateAI

Benign

0.41

PROVEAN

Benign

0.20

REVEL

Benign

0.19

Sift

Benign

0.38

Sift4G

Benign

0.54

Polyphen

0.0010

Vest4

0.024

MVP

0.62

MPC

0.12

ClinPred

0.0061

GERP RS

-6.1

Varity_R

0.076

gMVP

0.16

Mutation Taster

=99/1

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over