rs2088876638

Variant names:

• chrX-2908745-C-T
• rs2088876638
• NM_001669.4:c.1396G>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001669.4(ARSD):​c.1396G>A​(p.Ala466Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000551 in 1,089,538 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 21)
  • Exomes 𝑓: 0.0000055 (0 hom. 1 hem.)
• Consequence: ARSD NM_001669.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.32
• Publications: 0 publications found

Genes affected

ARSD (HGNC:717): (arylsulfatase D) The protein encoded by this gene is a member of the sulfatase family. Sulfatases are essential for the correct composition of bone and cartilage matrix. The encoded protein is postranslationally glycosylated and localized to the lysosome. This gene is located within a cluster of similar arylsulfatase genes on chromosome X. A related pseudogene has been identified in the pseudoautosomal region of chromosome Y. [provided by RefSeq, Jul 2011]

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.874

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001669.4. 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
	ARSD	NM_001669.4	MANE Select	c.1396G>A	p.Ala466Thr	missense	Exon 9 of 10	NP_001660.2	P51689-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARSD	ENST00000381154.6	TSL:1 MANE Select	c.1396G>A	p.Ala466Thr	missense	Exon 9 of 10	ENSP00000370546.1	P51689-1
	ARSD	ENST00000954947.1		c.1261G>A	p.Ala421Thr	missense	Exon 8 of 9	ENSP00000625006.1
	ARSD	ENST00000954948.1		c.961G>A	p.Ala321Thr	missense	Exon 6 of 7	ENSP00000625007.1

Frequencies

GnomAD3 genomes Cov.: 21

GnomAD4 exome AF: 0.00000551 AC: 6 AN: 1089538 Hom.: 0 Cov.: 31 AF XY: 0.00000281 AC XY: 1 AN XY: 356398

African (AFR) AF: 0.00 AC: 0 AN: 26148

American (AMR) AF: 0.0000292 AC: 1 AN: 34196

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18784

East Asian (EAS) AF: 0.0000334 AC: 1 AN: 29923

South Asian (SAS) AF: 0.00 AC: 0 AN: 52381

European-Finnish (FIN) AF: 0.0000248 AC: 1 AN: 40277

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4086

European-Non Finnish (NFE) AF: 0.00000239 AC: 2 AN: 838047

Other (OTH) AF: 0.0000219 AC: 1 AN: 45696

GnomAD4 genome Cov.: 21

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000416

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.030
CADD	Benign	16
DANN	Benign	0.88
DEOGEN2	Uncertain	0.69	D
FATHMM_MKL	Benign	0.68	D
LIST_S2	Benign	0.84	T
M_CAP	Pathogenic	0.29	D
MetaRNN	Pathogenic	0.87	D
MetaSVM	Uncertain	0.67	D
MutationAssessor	Benign	2.0	M
PhyloP100		6.3
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-3.2	D
REVEL	Uncertain	0.57
Sift	Benign	0.096	T
Sift4G	Benign	0.10	T
Polyphen		0.66	P
Vest4		0.54
MutPred		0.69		Loss of MoRF binding (P = 0.1288)
MVP		0.91
MPC		0.28
ClinPred		0.80	D
GERP RS		2.4
Varity_R		0.31
gMVP		0.83
Mutation Taster		=84/16	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2088876638; hg19: chrX-2826786;