rs1558878

Variant names:

• chr17-68368663-T-C
• rs1558878
• NM_001267727.2:c.820T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001267727.2(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_001267727.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.255
• Publications: 30 publications found

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

ACMG classification

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARSG	NM_001267727.2	c.820T>C	p.Trp274Arg	missense_variant	Exon 7 of 12	ENST00000621439.5	NP_001254656.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARSG	ENST00000621439.5	c.820T>C	p.Trp274Arg	missense_variant	Exon 7 of 12	5	NM_001267727.2	ENSP00000480910.1
ARSG	ENST00000448504.6	c.820T>C	p.Trp274Arg	missense_variant	Exon 7 of 12	1		ENSP00000407193.2
ARSG	ENST00000452479.6	c.328T>C	p.Trp110Arg	missense_variant	Exon 6 of 11	5		ENSP00000413953.2
ARSG	ENST00000582154.5	n.578T>C		non_coding_transcript_exon_variant	Exon 5 of 10	2

Frequencies

GnomAD3 genomes AF: 0.436 AC: 66295 AN: 152126 Hom.: 14942 Cov.: 34

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

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.: 53 AF XY: 0.474 AC XY: 344753 AN XY: 726758

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

GnomAD4 genome AF: 0.436 AC: 66316 AN: 152244 Hom.: 14939 Cov.: 34 AF XY: 0.434 AC XY: 32343 AN XY: 74452

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

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

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

May 04, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Usher syndrome, type 4 Benign:1

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.049
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	8.4
DANN	Benign	0.46
DEOGEN2	Benign	0.28	T;T;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.017	N
LIST_S2	Benign	0.014	.;T;T
MetaRNN	Benign	0.000059	T;T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	-1.3	N;N;.
PhyloP100		0.26
PrimateAI	Benign	0.32	T
REVEL	Benign	0.073
Sift4G	Benign	1.0	T;T;T
Polyphen		0.0	B;B;.
Vest4		0.016
MutPred		0.22		Gain of disorder (P = 0.0088);Gain of disorder (P = 0.0088);.;
MPC		0.57
ClinPred		0.0053	T
GERP RS		4.3
Varity_R		0.093
gMVP		0.77
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1558878; hg19: chr17-66364804; COSMIC: COSV71593276;