rs1558876

Positions:

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP3BP6_Very_StrongBA1

The NM_001267727.2(ARSG):c.707C>G(p.Thr236Ser) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.411 in 1,610,820 control chromosomes in the GnomAD database, including 140,933 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.36 ( 10734 hom., cov: 33)

Exomes 𝑓: 0.42 ( 130199 hom. )

Consequence

ARSG
NM_001267727.2 missense, splice_region

Scores

Clinical Significance

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

Conservation

PhyloP100: 2.03

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -15 ACMG points.

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

BP6

Variant 17-68368550-C-G is Benign according to our data. Variant chr17-68368550-C-G is described in ClinVar as [Benign]. Clinvar id is 1166453.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.434 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARSG	NM_001267727.2 linkuse as main transcript	c.707C>G	p.Thr236Ser	missense_variant, splice_region_variant	7/12	ENST00000621439.5	NP_001254656.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
ARSG	ENST00000621439.5 linkuse as main transcript	c.707C>G	p.Thr236Ser	missense_variant, splice_region_variant	7/12	5	NM_001267727.2	ENSP00000480910	P1
ARSG	ENST00000448504.6 linkuse as main transcript	c.707C>G	p.Thr236Ser	missense_variant, splice_region_variant	7/12	1		ENSP00000407193	P1
ARSG	ENST00000452479.6 linkuse as main transcript	c.215C>G	p.Thr72Ser	missense_variant, splice_region_variant	6/11	5		ENSP00000413953
ARSG	ENST00000582154.5 linkuse as main transcript	n.465C>G		splice_region_variant, non_coding_transcript_exon_variant	5/10	2

Frequencies

GnomAD3 genomes

AF:

0.361

AC:

54787

AN:

151956

Hom.:

10736

Cov.:

show subpopulations

Gnomad AFR

AF:

0.220

Gnomad AMI

AF:

0.503

Gnomad AMR

AF:

0.385

Gnomad ASJ

AF:

0.415

Gnomad EAS

AF:

0.135

Gnomad SAS

AF:

0.361

Gnomad FIN

AF:

0.456

Gnomad MID

AF:

0.395

Gnomad NFE

AF:

0.438

Gnomad OTH

AF:

0.363

GnomAD3 exomes

AF:

0.383

AC:

95369

AN:

249220

Hom.:

19407

AF XY:

0.387

AC XY:

52117

AN XY:

134692

show subpopulations

Gnomad AFR exome

AF:

0.210

Gnomad AMR exome

AF:

0.409

Gnomad ASJ exome

AF:

0.403

Gnomad EAS exome

AF:

0.130

Gnomad SAS exome

AF:

0.364

Gnomad FIN exome

AF:

0.458

Gnomad NFE exome

AF:

0.428

Gnomad OTH exome

AF:

0.401

GnomAD4 exome

AF:

0.417

AC:

607924

AN:

1458746

Hom.:

130199

Cov.:

AF XY:

0.417

AC XY:

302362

AN XY:

725670

show subpopulations

Gnomad4 AFR exome

AF:

0.214

Gnomad4 AMR exome

AF:

0.406

Gnomad4 ASJ exome

AF:

0.402

Gnomad4 EAS exome

AF:

0.150

Gnomad4 SAS exome

AF:

0.364

Gnomad4 FIN exome

AF:

0.462

Gnomad4 NFE exome

AF:

0.436

Gnomad4 OTH exome

AF:

0.394

GnomAD4 genome

AF:

0.360

AC:

54796

AN:

152074

Hom.:

10734

Cov.:

AF XY:

0.360

AC XY:

26735

AN XY:

74330

show subpopulations

Gnomad4 AFR

AF:

0.220

Gnomad4 AMR

AF:

0.385

Gnomad4 ASJ

AF:

0.415

Gnomad4 EAS

AF:

0.134

Gnomad4 SAS

AF:

0.361

Gnomad4 FIN

AF:

0.456

Gnomad4 NFE

AF:

0.438

Gnomad4 OTH

AF:

0.363

Alfa

AF:

0.414

Hom.:

10151

Bravo

AF:

0.351

TwinsUK

AF:

0.436

AC:

1616

ALSPAC

AF:

0.435

AC:

1677

ESP6500AA

AF:

0.223

AC:

984

ESP6500EA

AF:

0.438

AC:

3769

ExAC

AF:

0.378

AC:

45940

Asia WGS

AF:

0.264

AC:

921

AN:

3478

EpiCase

AF:

0.429

EpiControl

AF:

0.422

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 04, 2021	- -

Usher syndrome, type 4

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.068

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.30

CADD

Benign

DANN

Benign

0.68

DEOGEN2

Benign

0.28

T;T;T

Eigen

Benign

-0.38

Eigen_PC

Benign

-0.25

FATHMM_MKL

Benign

0.27

LIST_S2

Benign

0.39

.;T;T

MetaRNN

Benign

0.0014

T;T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

0.25

N;N;.

MutationTaster

Benign

0.99

P;P

PrimateAI

Benign

0.30

REVEL

Benign

0.029

Sift4G

Benign

0.67

T;T;T

Polyphen

0.026

B;B;.

Vest4

0.038

MutPred

0.10

Gain of helix (P = 0.0199);Gain of helix (P = 0.0199);.;

MPC

0.29

ClinPred

0.0039

GERP RS

4.2

Varity_R

0.087

gMVP

0.41

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.71

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.71

Position offset: 1

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