X-2949663-A-C

Variant names:

• chrX-2949663-A-C
• rs35274634
• NM_000047.3:c.495T>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP6_Moderate

The NM_000047.3(ARSL):​c.495T>G​(p.His165Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Benign (★). Synonymous variant affecting the same amino acid position (i.e. H165H) has been classified as Benign.

• Frequency: Genomes: not found (cov: 22)
• Consequence: ARSL NM_000047.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.782
• Publications: 1 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: Orphanet, ClinGen, G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant X-2949663-A-C is Benign according to our data. Variant chrX-2949663-A-C is described in ClinVar as Benign. ClinVar VariationId is 157733.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARSL	NM_000047.3	c.495T>G	p.His165Gln	missense_variant	Exon 6 of 11	ENST00000381134.9	NP_000038.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARSL	ENST00000381134.9	c.495T>G	p.His165Gln	missense_variant	Exon 6 of 11	1	NM_000047.3	ENSP00000370526.3

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 22

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.58
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
CADD	Benign	6.0
DANN	Benign	0.88
DEOGEN2	Uncertain	0.77	D;.;D;.
FATHMM_MKL	Benign	0.24	N
LIST_S2	Benign	0.84	T;T;T;D
M_CAP	Pathogenic	0.69	D
MetaRNN	Uncertain	0.74	D;D;D;D
MetaSVM	Uncertain	0.70	D
MutationAssessor	Benign	0.81	.;.;L;.
PhyloP100		-0.78
PrimateAI	Benign	0.47	T
PROVEAN	Pathogenic	-7.5	D;D;D;D
REVEL	Uncertain	0.53
Sift	Benign	0.15	T;T;T;T
Sift4G	Benign	0.17	T;T;T;.
Polyphen		1.0	D;D;D;.
Vest4		0.56
MutPred		0.59		Loss of disorder (P = 0.1231);.;.;.;
MVP		0.79
MPC		1.3
ClinPred		0.43	T
GERP RS		-7.1
Varity_R		0.46
gMVP		0.85
Mutation Taster		=82/18	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs35274634; hg19: chrX-2867704;