17-68368550-C-A

Variant names:

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

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PVS1_Strong PM2

The NM_001352903.2(ARSG):​c.705-1C>A variant causes a splice acceptor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,460,750 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: ARSG NM_001352903.2 splice_acceptor, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.03
• Publications: 0 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp
• Usher syndrome type 3

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.1231746 fraction of the gene. Cryptic splice site detected, with MaxEntScore 8.3, offset of -3, new splice context is: tcttggttctcctgtttcAGcaa. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001352903.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARSG	NM_001267727.2	MANE Select	c.707C>A	p.Thr236Asn	missense splice_region	Exon 7 of 12	NP_001254656.1	Q96EG1
	ARSG	NM_001352899.2		c.707C>A	p.Thr236Asn	missense splice_region	Exon 7 of 13	NP_001339828.1	Q96EG1
	ARSG	NM_001352900.2		c.707C>A	p.Thr236Asn	missense splice_region	Exon 7 of 12	NP_001339829.1	Q96EG1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARSG	ENST00000621439.5	TSL:5 MANE Select	c.707C>A	p.Thr236Asn	missense splice_region	Exon 7 of 12	ENSP00000480910.1	Q96EG1
	ARSG	ENST00000448504.6	TSL:1	c.707C>A	p.Thr236Asn	missense splice_region	Exon 7 of 12	ENSP00000407193.2	Q96EG1
	ARSG	ENST00000452479.6	TSL:5	c.215C>A	p.Thr72Asn	missense splice_region	Exon 6 of 11	ENSP00000413953.2	J9JIG6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1460750 Hom.: 0 Cov.: 38 AF XY: 0.00000275 AC XY: 2 AN XY: 726686

African (AFR) AF: 0.00 AC: 0 AN: 33450

American (AMR) AF: 0.00 AC: 0 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86184

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53384

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5232

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111696

Other (OTH) AF: 0.00 AC: 0 AN: 60296

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.090	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	18
DANN	Benign	0.87
DEOGEN2	Benign	0.28	T
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.37
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.56	T
M_CAP	Benign	0.0094	T
MetaRNN	Benign	0.097	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.24	N
PhyloP100		2.0
PrimateAI	Benign	0.33	T
REVEL	Benign	0.065
Sift4G	Benign	0.54	T
Polyphen		0.0040	B
Vest4		0.11
MutPred		0.34		Gain of sheet (P = 0.0344)
MVP		0.68
MPC		0.37
ClinPred		0.84	D
GERP RS		4.2
Varity_R		0.10
gMVP		0.51
Mutation Taster		=86/14	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs1558876; hg19: chr17-66364691;