X-3076577-A-G

Variant names:

• chrX-3076577-A-G
• NM_001201539.2:c.191A>G

Variant summary

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

The NM_001201539.2(ARSF):​c.191A>G​(p.Glu64Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 22)
• Consequence: ARSF NM_001201539.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.35
• Publications: 0 publications found

Genes affected

ARSF (HGNC:721): (arylsulfatase F) This gene is a member of the sulfatase family, and more specifically, the arylsulfatase subfamily. Members of the subfamily share similarity in sequence and splice sites, and are clustered together on chromosome X, suggesting that they are derived from recent gene duplication events. Sulfatases are essential for the correct composition of bone and cartilage matrix. The activity of this protein, unlike that of arylsulfatase E, is not inhibited by warfarin. Multiple alternatively spliced variants, encoding the same protein, have been identified.[provided by RefSeq, Jan 2011]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARSF	NM_001201539.2	c.191A>G	p.Glu64Gly	missense_variant	Exon 4 of 11	ENST00000381127.6	NP_001188468.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARSF	ENST00000381127.6	c.191A>G	p.Glu64Gly	missense_variant	Exon 4 of 11	1	NM_001201539.2	ENSP00000370519.1
ARSF	ENST00000359361.2	c.191A>G	p.Glu64Gly	missense_variant	Exon 4 of 11	1		ENSP00000352319.2

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 22

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 15, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.191A>G (p.E64G) alteration is located in exon 4 (coding exon 3) of the ARSF gene. This alteration results from a A to G substitution at nucleotide position 191, causing the glutamic acid (E) at amino acid position 64 to be replaced by a glycine (G). 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	0.21
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.77	D;D
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.95	.;D
M_CAP	Benign	0.033	D
MetaRNN	Uncertain	0.64	D;D
MetaSVM	Uncertain	0.61	D
MutationAssessor	Benign	1.9	L;L
PhyloP100		7.3
PrimateAI	Benign	0.43	T
PROVEAN	Pathogenic	-5.8	D;D
REVEL	Uncertain	0.50
Sift	Benign	0.17	T;T
Sift4G	Benign	0.11	T;T
Polyphen		0.18	B;B
Vest4		0.42
MutPred		0.63		Gain of MoRF binding (P = 0.0251);Gain of MoRF binding (P = 0.0251);
MVP		0.56
MPC		0.22
ClinPred		0.96	D
GERP RS		2.6
Varity_R		0.27
gMVP		0.63
Mutation Taster		=84/16	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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-2994618;