chr17-68368550-C-A

Variant names:

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

Variant summary

Our verdict is Likely pathogenic. Variant got 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

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 Likely_pathogenic. Variant got 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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARSG	NM_001267727.2	c.707C>A	p.Thr236Asn	missense_variant, splice_region_variant	Exon 7 of 12	ENST00000621439.5	NP_001254656.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARSG	ENST00000621439.5	c.707C>A	p.Thr236Asn	missense_variant, splice_region_variant	Exon 7 of 12	5	NM_001267727.2	ENSP00000480910.1
ARSG	ENST00000448504.6	c.707C>A	p.Thr236Asn	missense_variant, splice_region_variant	Exon 7 of 12	1		ENSP00000407193.2
ARSG	ENST00000452479.6	c.215C>A	p.Thr72Asn	missense_variant, splice_region_variant	Exon 6 of 11	5		ENSP00000413953.2
ARSG	ENST00000582154.5	n.465C>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 5 of 10	2

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

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;T;T
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.37
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.56	.;T;T
M_CAP	Benign	0.0094	T
MetaRNN	Benign	0.097	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.24	N;N;.
PrimateAI	Benign	0.33	T
REVEL	Benign	0.065
Sift4G	Benign	0.54	T;T;T
Polyphen		0.0040	B;B;.
Vest4		0.11
MutPred		0.34		Gain of sheet (P = 0.0344);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

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-66364691;