17-68368550-C-G

Variant names:

• chr17-68368550-C-G
• rs1558876
• NM_001267727.2:c.707C>G

Variant summary

Our verdict is Benign. The variant received -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. 14/22 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 (★★).

• 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:4
• Conservation: PhyloP100: 2.03
• Publications: 24 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 -15 ACMG points.

• PP3: Splicing predictors support a deleterious 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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001267727.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARSG	NM_001267727.2	MANE Select	c.707C>G	p.Thr236Ser	missense splice_region	Exon 7 of 12	NP_001254656.1
	ARSG	NM_001352899.2		c.707C>G	p.Thr236Ser	missense splice_region	Exon 7 of 13	NP_001339828.1
	ARSG	NM_001352900.2		c.707C>G	p.Thr236Ser	missense splice_region	Exon 7 of 12	NP_001339829.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARSG	ENST00000621439.5	TSL:5 MANE Select	c.707C>G	p.Thr236Ser	missense splice_region	Exon 7 of 12	ENSP00000480910.1
	ARSG	ENST00000448504.6	TSL:1	c.707C>G	p.Thr236Ser	missense splice_region	Exon 7 of 12	ENSP00000407193.2
	ARSG	ENST00000452479.6	TSL:5	c.215C>G	p.Thr72Ser	missense splice_region	Exon 6 of 11	ENSP00000413953.2

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

GnomAD2 exomes AF: 0.383 AC: 95369 AN: 249220 AF XY: 0.387

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 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

African (AFR) AF: 0.214 AC: 7160 AN: 33388

American (AMR) AF: 0.406 AC: 18105 AN: 44556

Ashkenazi Jewish (ASJ) AF: 0.402 AC: 10485 AN: 26102

East Asian (EAS) AF: 0.150 AC: 5931 AN: 39646

South Asian (SAS) AF: 0.364 AC: 31303 AN: 86070

European-Finnish (FIN) AF: 0.462 AC: 24641 AN: 53328

Middle Eastern (MID) AF: 0.383 AC: 1995 AN: 5208

European-Non Finnish (NFE) AF: 0.436 AC: 484589 AN: 1110214

Other (OTH) AF: 0.394 AC: 23715 AN: 60234

GnomAD4 genome AF: 0.360 AC: 54796 AN: 152074 Hom.: 10734 Cov.: 33 AF XY: 0.360 AC XY: 26735 AN XY: 74330

African (AFR) AF: 0.220 AC: 9112 AN: 41492

American (AMR) AF: 0.385 AC: 5873 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.415 AC: 1439 AN: 3464

East Asian (EAS) AF: 0.134 AC: 694 AN: 5164

South Asian (SAS) AF: 0.361 AC: 1741 AN: 4822

European-Finnish (FIN) AF: 0.456 AC: 4821 AN: 10580

Middle Eastern (MID) AF: 0.408 AC: 119 AN: 292

European-Non Finnish (NFE) AF: 0.438 AC: 29772 AN: 67974

Other (OTH) AF: 0.363 AC: 766 AN: 2108

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

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Usher syndrome, type 4 (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.25
FATHMM_MKL	Benign	0.27	N
LIST_S2	Benign	0.39	T
MetaRNN	Benign	0.0014	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.25	N
PhyloP100		2.0
PrimateAI	Benign	0.30	T
REVEL	Benign	0.029
Sift4G	Benign	0.67	T
Polyphen		0.026	B
Vest4		0.038
MutPred		0.10		Gain of helix (P = 0.0199)
MPC		0.29
ClinPred		0.0039	T
GERP RS		4.2
Varity_R		0.087
gMVP		0.41
Mutation Taster		=94/6	polymorphism (auto)

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

Other links and lift over

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