chrX-2908724-C-G

Variant names:

• chrX-2908724-C-G
• rs757272441
• NM_001669.4:c.1417G>C

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_001669.4(ARSD):​c.1417G>C​(p.Asp473His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000042 in 1,191,879 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000090 (0 hom., 0 hem., cov: 22)
  • Exomes 𝑓: 0.0000037 (0 hom. 2 hem.)
• Consequence: ARSD NM_001669.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.759
• 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: Likely_benign. The variant received -4 ACMG points.

• BS2: High Hemizygotes in GnomAdExome4 at 2 gene

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.1417G>C	p.Asp473His	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.1417G>C	p.Asp473His	missense	Exon 9 of 10	ENSP00000370546.1	P51689-1
	ARSD	ENST00000954947.1		c.1282G>C	p.Asp428His	missense	Exon 8 of 9	ENSP00000625006.1
	ARSD	ENST00000954948.1		c.982G>C	p.Asp328His	missense	Exon 6 of 7	ENSP00000625007.1

Frequencies

GnomAD3 genomes AF: 0.00000899 AC: 1 AN: 111269 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000388

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000370 AC: 4 AN: 1080557 Hom.: 0 Cov.: 31 AF XY: 0.00000570 AC XY: 2 AN XY: 350697

African (AFR) AF: 0.00 AC: 0 AN: 26028

American (AMR) AF: 0.00 AC: 0 AN: 33504

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18057

East Asian (EAS) AF: 0.00 AC: 0 AN: 29793

South Asian (SAS) AF: 0.0000592 AC: 3 AN: 50642

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39873

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4034

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 833253

Other (OTH) AF: 0.0000220 AC: 1 AN: 45373

GnomAD4 genome AF: 0.00000898 AC: 1 AN: 111322 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 33512

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 30649

American (AMR) AF: 0.00 AC: 0 AN: 10417

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2643

East Asian (EAS) AF: 0.00 AC: 0 AN: 3533

South Asian (SAS) AF: 0.000389 AC: 1 AN: 2569

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6029

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 217

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53060

Other (OTH) AF: 0.00 AC: 0 AN: 1522

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

ExAC AF: 0.0000165 AC: 2

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	0.16
BayesDel_addAF	Uncertain	0.017	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	17
DANN	Benign	0.96
DEOGEN2	Uncertain	0.70	D
FATHMM_MKL	Benign	0.074	N
LIST_S2	Benign	0.53	T
M_CAP	Benign	0.055	D
MetaRNN	Uncertain	0.53	D
MetaSVM	Uncertain	0.35	D
MutationAssessor	Uncertain	2.5	M
PhyloP100		0.76
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-5.0	D
REVEL	Benign	0.26
Sift	Uncertain	0.018	D
Sift4G	Uncertain	0.011	D
Polyphen		0.98	D
Vest4		0.15
MutPred		0.48		Gain of MoRF binding (P = 0.0404)
MVP		0.95
MPC		0.22
ClinPred		0.84	D
GERP RS		0.43
Varity_R		0.31
gMVP		0.64
Mutation Taster		=88/12	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

dbSNP: rs757272441; hg19: chrX-2826765;