chr17-68368550-C-T

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001267727.2(ARSG):​c.707C>T​(p.Thr236Ile) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000821 in 1,460,750 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T236S) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: ARSG NM_001267727.2 missense, splice_region
• Clinical Significance: Not reported in ClinVar
• 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.16415167).

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>T	p.Thr236Ile	missense splice_region	Exon 7 of 12	NP_001254656.1
	ARSG	NM_001352899.2		c.707C>T	p.Thr236Ile	missense splice_region	Exon 7 of 13	NP_001339828.1
	ARSG	NM_001352900.2		c.707C>T	p.Thr236Ile	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>T	p.Thr236Ile	missense splice_region	Exon 7 of 12	ENSP00000480910.1
	ARSG	ENST00000448504.6	TSL:1	c.707C>T	p.Thr236Ile	missense splice_region	Exon 7 of 12	ENSP00000407193.2
	ARSG	ENST00000452479.6	TSL:5	c.215C>T	p.Thr72Ile	missense splice_region	Exon 6 of 11	ENSP00000413953.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000401 AC: 1 AN: 249220 AF XY: 0.00000742

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000546

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000821 AC: 12 AN: 1460750 Hom.: 0 Cov.: 38 AF XY: 0.0000138 AC XY: 10 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: 0.000302 AC: 12 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: 0.00 AC: 0 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	0.084
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.53	D
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.14
FATHMM_MKL	Benign	0.24	N
LIST_S2	Benign	0.60	T
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-0.69	T
MutationAssessor	Benign	1.8	L
PhyloP100		2.0
PrimateAI	Benign	0.35	T
REVEL	Benign	0.073
Sift4G	Benign	0.17	T
Polyphen		0.021	B
Vest4		0.21
MutPred		0.38		Gain of helix (P = 0.0425)
MVP		0.82
MPC		0.36
ClinPred		0.13	T
GERP RS		4.2
Varity_R		0.14
gMVP		0.49

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: rs1558876; hg19: chr17-66364691;