17-68368663-T-C

Position:

• chr17-68368663-T-C

Variant summary

Our verdict is Benign. Variant got -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. 14/19 in silico tools predict a benign outcome for this variant. 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 0.44 (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

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -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 id 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/exons	MANE	Protein	UniProt
ARSG	NM_001267727.2	c.820T>C	p.Trp274Arg	missense_variant	7/12	ENST00000621439.5	NP_001254656.1

Ensembl

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

GnomAD3 exomes AF: 0.445 AC: 111488 AN: 250300 Hom.: 25819 AF XY: 0.449 AC XY: 60675 AN XY: 135282

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 SAS exome AF: 0.408

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

Gnomad4 AFR exome AF: 0.330

Gnomad4 AMR exome AF: 0.447

Gnomad4 ASJ exome AF: 0.465

Gnomad4 EAS exome AF: 0.240

Gnomad4 SAS exome AF: 0.410

Gnomad4 FIN exome AF: 0.499

Gnomad4 NFE exome AF: 0.494

Gnomad4 OTH exome AF: 0.458

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

Gnomad4 AFR AF: 0.338

Gnomad4 AMR AF: 0.439

Gnomad4 ASJ AF: 0.477

Gnomad4 EAS AF: 0.243

Gnomad4 SAS AF: 0.403

Gnomad4 FIN AF: 0.492

Gnomad4 NFE AF: 0.498

Gnomad4 OTH AF: 0.432

Alfa AF: 0.479 Hom.: 45721

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

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	0.049
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;.
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

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

LitVar

Other links and lift over

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