chrX-2934949-T-A

Variant names:

• chrX-2934949-T-A
• rs772926810
• NM_000047.3:c.1653A>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BP6_Moderate BP7 BS2_Supporting

The NM_000047.3(ARSL):​c.1653A>T​(p.Thr551Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000497 in 1,208,379 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0000090 (0 hom., 1 hem., cov: 22)
  • Exomes 𝑓: 0.0000046 (0 hom. 2 hem.)
• Consequence: ARSL NM_000047.3 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.15
• Publications: 0 publications found

Genes affected

ARSL (HGNC:719): (arylsulfatase L) Arylsulfatase E is a member of the sulfatase family. It is glycosylated postranslationally and localized to the golgi apparatus. Sulfatases are essential for the correct composition of bone and cartilage matrix. X-linked chondrodysplasia punctata, a disease characterized by abnormalities in cartilage and bone development, has been linked to mutations in this gene. Alternative splicing results in multiple transcript variants. A pseudogene related to this gene is located on the Y chromosome. [provided by RefSeq, Sep 2013]

ARSL Gene-Disease associations (from GenCC):

• X-linked chondrodysplasia punctata 1

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, G2P, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant X-2934949-T-A is Benign according to our data. Variant chrX-2934949-T-A is described in ClinVar as Likely_benign. ClinVar VariationId is 1683176.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-2.15 with no splicing effect.
• BS2: High Hemizygotes in GnomAdExome4 at 2 XL geneVariant has number of hemizygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000047.3. 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
	ARSL	NM_000047.3	MANE Select	c.1653A>T	p.Thr551Thr	synonymous	Exon 11 of 11	NP_000038.2	P51690
	ARSL	NM_001282628.2		c.1728A>T	p.Thr576Thr	synonymous	Exon 12 of 12	NP_001269557.1	F5GYY5
	ARSL	NM_001369080.1		c.1728A>T	p.Thr576Thr	synonymous	Exon 12 of 12	NP_001356009.1	F5GYY5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARSL	ENST00000381134.9	TSL:1 MANE Select	c.1653A>T	p.Thr551Thr	synonymous	Exon 11 of 11	ENSP00000370526.3	P51690
	ARSL	ENST00000545496.6	TSL:2	c.1728A>T	p.Thr576Thr	synonymous	Exon 12 of 12	ENSP00000441417.1	F5GYY5
	ARSL	ENST00000672027.1		c.1728A>T	p.Thr576Thr	synonymous	Exon 12 of 12	ENSP00000500220.1	F5GYY5

Frequencies

GnomAD3 genomes AF: 0.00000899 AC: 1 AN: 111244 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: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000189

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000551 AC: 1 AN: 181630 AF XY: 0.0000151

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000124

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000456 AC: 5 AN: 1097135 Hom.: 0 Cov.: 32 AF XY: 0.00000552 AC XY: 2 AN XY: 362633

African (AFR) AF: 0.00 AC: 0 AN: 26385

American (AMR) AF: 0.00 AC: 0 AN: 35162

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19363

East Asian (EAS) AF: 0.00 AC: 0 AN: 30194

South Asian (SAS) AF: 0.00 AC: 0 AN: 54014

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40503

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3855

European-Non Finnish (NFE) AF: 0.00000594 AC: 5 AN: 841635

Other (OTH) AF: 0.00 AC: 0 AN: 46024

GnomAD4 genome AF: 0.00000899 AC: 1 AN: 111244 Hom.: 0 Cov.: 22 AF XY: 0.0000299 AC XY: 1 AN XY: 33470

African (AFR) AF: 0.00 AC: 0 AN: 30578

American (AMR) AF: 0.00 AC: 0 AN: 10425

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2644

East Asian (EAS) AF: 0.00 AC: 0 AN: 3531

South Asian (SAS) AF: 0.00 AC: 0 AN: 2607

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6011

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 240

European-Non Finnish (NFE) AF: 0.0000189 AC: 1 AN: 53036

Other (OTH) AF: 0.00 AC: 0 AN: 1488

Alfa AF: 0.0000868 Hom.: 1

Bravo AF: 0.0000151

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Chondrodysplasia punctata, brachytelephalangic, autosomal (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.10
DANN	Benign	0.39
PhyloP100		-2.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs772926810; hg19: chrX-2852990;