chrX-2908745-C-T

Position:

• chrX-2908745-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The ENST00000381154.6(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 ENST00000381154.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.32

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]

ARSD (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARSD	NM_001669.4	c.1396G>A	p.Ala466Thr	missense_variant	9/10	ENST00000381154.6	NP_001660.2
ARSD	XM_005274514.3	c.1261G>A	p.Ala421Thr	missense_variant	8/9		XP_005274571.1
ARSD	XM_047442108.1	c.1258G>A	p.Ala420Thr	missense_variant	9/10		XP_047298064.1
ARSD	XM_005274515.3	c.1396G>A	p.Ala466Thr	missense_variant	9/10		XP_005274572.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARSD	ENST00000381154.6	c.1396G>A	p.Ala466Thr	missense_variant	9/10	1	NM_001669.4	ENSP00000370546.1
ARSD	ENST00000458014.1	c.202G>A	p.Ala68Thr	missense_variant	2/4	3		ENSP00000409180.1
ARSD	ENST00000495294.1	n.179G>A		non_coding_transcript_exon_variant	2/3	2

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000292

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000334

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000248

Gnomad4 NFE exome AF: 0.00000239

Gnomad4 OTH exome AF: 0.0000219

GnomAD4 genome Cov.: 21

Bravo AF: 0.0000416

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 20, 2023

The c.1396G>A (p.A466T) alteration is located in exon 9 (coding exon 9) of the ARSD gene. This alteration results from a G to A substitution at nucleotide position 1396, causing the alanine (A) at amino acid position 466 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

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;T
M_CAP	Pathogenic	0.29	D
MetaRNN	Pathogenic	0.87	D;D
MetaSVM	Uncertain	0.67	D
MutationAssessor	Benign	2.0	M;.
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-3.2	D;D
REVEL	Uncertain	0.57
Sift	Benign	0.096	T;T
Sift4G	Benign	0.10	T;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

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

Publications

LitVar

Other links and lift over

dbSNP: rs2088876638; hg19: chrX-2826786;