rs1558878

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_014960.5(ARSG):c.820T>C(p.Trp274Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.471 in 1,613,180 control chromosomes in the GnomAD database, including 182,582 homozygotes. 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. W274Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.44 ( 14939 hom., cov: 34)

Exomes 𝑓: 0.47 ( 167643 hom. )

Consequence

ARSG
NM_014960.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.255

Publications

30 publications found

Variant links:

Genes affected

ARSG (HGNC:24102): (arylsulfatase G) The protein encoded by this gene belongs to the sulfatase enzyme family. Sulfatases hydrolyze sulfate esters from sulfated steroids, carbohydrates, proteoglycans, and glycolipids. They are involved in hormone biosynthesis, modulation of cell signaling, and degradation of macromolecules. This protein displays arylsulfatase activity at acidic pH, as is typical of lysosomal sulfatases, and has been shown to localize in the lysosomes. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Jun 2012]

ARSG Gene-Disease associations (from GenCC):

Usher syndrome, type 4
Inheritance: AR Classification: STRONG, MODERATE, LIMITED Submitted by: Genomics England PanelApp, G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
Usher syndrome type 3
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ARSG 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=5.887314E-5).

BP6

Variant 17-68368663-T-C is Benign according to our data. Variant chr17-68368663-T-C is described in ClinVar as Benign. ClinVar VariationId is 1166454.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.494 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014960.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ARSG	NM_001267727.2	MANE Select	c.820T>C	p.Trp274Arg	missense	Exon 7 of 12	NP_001254656.1
ARSG	NM_001352899.2		c.820T>C	p.Trp274Arg	missense	Exon 7 of 13	NP_001339828.1
ARSG	NM_001352900.2		c.820T>C	p.Trp274Arg	missense	Exon 7 of 12	NP_001339829.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ARSG	ENST00000621439.5	TSL:5 MANE Select	c.820T>C	p.Trp274Arg	missense	Exon 7 of 12	ENSP00000480910.1
ARSG	ENST00000448504.6	TSL:1	c.820T>C	p.Trp274Arg	missense	Exon 7 of 12	ENSP00000407193.2
ARSG	ENST00000452479.6	TSL:5	c.328T>C	p.Trp110Arg	missense	Exon 6 of 11	ENSP00000413953.2

Frequencies

GnomAD3 genomes

AF:

0.436

AC:

66295

AN:

152126

Hom.:

14942

Cov.:

show subpopulations

Gnomad AFR

AF:

0.338

Gnomad AMI

AF:

0.589

Gnomad AMR

AF:

0.440

Gnomad ASJ

AF:

0.477

Gnomad EAS

AF:

0.244

Gnomad SAS

AF:

0.403

Gnomad FIN

AF:

0.492

Gnomad MID

AF:

0.487

Gnomad NFE

AF:

0.498

Gnomad OTH

AF:

0.432

GnomAD2 exomes

AF:

0.445

AC:

111488

AN:

250300

AF XY:

0.449

show subpopulations

Gnomad AFR exome

AF:

0.333

Gnomad AMR exome

AF:

0.448

Gnomad ASJ exome

AF:

0.470

Gnomad EAS exome

AF:

0.241

Gnomad FIN exome

AF:

0.495

Gnomad NFE exome

AF:

0.491

Gnomad OTH exome

AF:

0.465

GnomAD4 exome

AF:

0.475

AC:

693749

AN:

1460936

Hom.:

167643

Cov.:

AF XY:

0.474

AC XY:

344753

AN XY:

726758

show subpopulations

African (AFR)

AF:

0.330

AC:

11039

AN:

33432

American (AMR)

AF:

0.447

AC:

19894

AN:

44510

Ashkenazi Jewish (ASJ)

AF:

0.465

AC:

12145

AN:

26094

East Asian (EAS)

AF:

0.240

AC:

9513

AN:

39648

South Asian (SAS)

AF:

0.410

AC:

35346

AN:

86150

European-Finnish (FIN)

AF:

0.499

AC:

26655

AN:

53408

Middle Eastern (MID)

AF:

0.472

AC:

2719

AN:

5762

European-Non Finnish (NFE)

AF:

0.494

AC:

548820

AN:

1111566

Other (OTH)

AF:

0.458

AC:

27618

AN:

60366

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.452

Heterozygous variant carriers

21362

42725

64087

85450

106812

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

15818

31636

47454

63272

79090

<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:

0.436

AC:

66316

AN:

152244

Hom.:

14939

Cov.:

AF XY:

0.434

AC XY:

32343

AN XY:

74452

show subpopulations

African (AFR)

AF:

0.338

AC:

14039

AN:

41522

American (AMR)

AF:

0.439

AC:

6720

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.477

AC:

1656

AN:

3470

East Asian (EAS)

AF:

0.243

AC:

1262

AN:

5184

South Asian (SAS)

AF:

0.403

AC:

1947

AN:

4826

European-Finnish (FIN)

AF:

0.492

AC:

5222

AN:

10616

Middle Eastern (MID)

AF:

0.493

AC:

145

AN:

294

European-Non Finnish (NFE)

AF:

0.498

AC:

33876

AN:

68006

Other (OTH)

AF:

0.432

AC:

913

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1979

3957

5936

7914

9893

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

624

1248

1872

2496

3120

<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:

0.473

Hom.:

85448

Bravo

AF:

0.429

TwinsUK

AF:

0.487

AC:

1804

ALSPAC

AF:

0.485

AC:

1870

ESP6500AA

AF:

0.346

AC:

1524

ESP6500EA

AF:

0.497

AC:

4276

ExAC

AF:

0.444

AC:

53872

Asia WGS

AF:

0.333

AC:

1160

AN:

3478

EpiCase

AF:

0.492

EpiControl

AF:

0.486

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Usher syndrome, type 4 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.049

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.34

CADD

Benign

8.4

(source)

DANN

Benign

0.46

DEOGEN2

Benign

0.28

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.017

LIST_S2

Benign

0.014

MetaRNN

Benign

0.000059

MetaSVM

Benign

-0.91

MutationAssessor

Benign

-1.3

PhyloP100

0.26

PrimateAI

Benign

0.32

REVEL

Benign

0.073

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.016

MutPred

0.22

Gain of disorder (P = 0.0088)

MPC

0.57

ClinPred

0.0053

GERP RS

4.3

Varity_R

0.093

gMVP

0.77

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