X-2907579-C-T

Variant names:

• chrX-2907579-C-T
• NM_001669.4:c.1474G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001669.4(ARSD):​c.1474G>A​(p.Ala492Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: ARSD NM_001669.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0730
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.31846812).

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.1474G>A	p.Ala492Thr	missense	Exon 10 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.1474G>A	p.Ala492Thr	missense	Exon 10 of 10	ENSP00000370546.1	P51689-1
	ARSD	ENST00000954947.1		c.1339G>A	p.Ala447Thr	missense	Exon 9 of 9	ENSP00000625006.1
	ARSD	ENST00000954948.1		c.1039G>A	p.Ala347Thr	missense	Exon 7 of 7	ENSP00000625007.1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1022075 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 321167

African (AFR) AF: 0.00 AC: 0 AN: 24399

American (AMR) AF: 0.00 AC: 0 AN: 23788

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15554

East Asian (EAS) AF: 0.00 AC: 0 AN: 27957

South Asian (SAS) AF: 0.00 AC: 0 AN: 43550

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 36693

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3832

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 803478

Other (OTH) AF: 0.00 AC: 0 AN: 42824

GnomAD4 genome Cov.: 24

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	0.081
BayesDel_addAF	Benign	-0.097	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	5.3
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.57	D
FATHMM_MKL	Benign	0.049	N
LIST_S2	Benign	0.72	T
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.32	T
MetaSVM	Benign	-0.48	T
MutationAssessor	Benign	1.8	L
PhyloP100		0.073
PrimateAI	Benign	0.41	T
PROVEAN	Uncertain	-2.8	D
REVEL	Benign	0.28
Sift	Benign	0.41	T
Sift4G	Benign	0.58	T
Polyphen		0.59	P
Vest4		0.086
MutPred		0.51		Gain of glycosylation at A492 (P = 0.0718)
MVP		0.84
MPC		0.29
ClinPred		0.86	D
GERP RS		2.1
Varity_R		0.12
gMVP		0.49
Mutation Taster		=94/6	polymorphism

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

hg19: chrX-2825620;