rs1558876

chr17-68368550-C-Gchr17-68368550-C-T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP3 BP6_Very_Strong BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.03

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]

ACMG classification

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	UniProt
ARSG	NM_001267727.2	c.707C>G	p.Thr236Ser	missense_variant, splice_region_variant	7/12	ENST00000621439.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARSG	ENST00000621439.5	c.707C>G	p.Thr236Ser	missense_variant, splice_region_variant	7/12	5	NM_001267727.2	P1
ARSG	ENST00000448504.6	c.707C>G	p.Thr236Ser	missense_variant, splice_region_variant	7/12	1		P1
ARSG	ENST00000452479.6	c.215C>G	p.Thr72Ser	missense_variant, splice_region_variant	6/11	5
ARSG	ENST00000582154.5	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.: 33

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

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.: 38 AF XY: 0.417 AC XY: 302362 AN XY: 725670

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.: 33 AF XY: 0.360 AC XY: 26735 AN XY: 74330

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:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 04, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

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	T
BayesDel_noAF	Benign	-0.30
Cadd	Benign	23
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	N
MetaRNN	Benign	0.0014	T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.25	N;N;.
MutationTaster	Benign	0.99	P;P
PrimateAI	Benign	0.30	T
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	T
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

Other links and lift over

dbSNP: rs1558876; hg19: chr17-66364691; COSMIC: COSV71592885;