X-3010133-C-T

Variant names:

• chrX-3010133-C-T
• rs148749736
• NM_001011719.2:c.196C>T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PP3_Moderate BP6 BS2

The NM_001011719.2(ARSH):​c.196C>T​(p.Arg66Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000171 in 1,209,371 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 73 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000098 (0 hom., 3 hem., cov: 22)
  • Exomes 𝑓: 0.00018 (0 hom. 70 hem.)
• Consequence: ARSH NM_001011719.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 0.340

Genes affected

ARSH (HGNC:32488): (arylsulfatase family member H) Sulfatases, such as ARSH, hydrolyze sulfate esters from sulfated steroids, carbohydrates, proteoglycans, and glycolipids. They are involved in hormone biosynthesis, modulation of cell signaling, and degradation of macromolecules (Sardiello et al., 2005 [PubMed 16174644]).[supplied by OMIM, Mar 2008]

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.897
• BP6: Variant X-3010133-C-T is Benign according to our data. Variant chrX-3010133-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2362277.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}. Variant chrX-3010133-C-T is described in Lovd as [Likely_benign].
• BS2: High Hemizygotes in GnomAd4 at 3 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARSH	NM_001011719.2	c.196C>T	p.Arg66Trp	missense_variant	Exon 2 of 9	ENST00000381130.3	NP_001011719.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARSH	ENST00000381130.3	c.196C>T	p.Arg66Trp	missense_variant	Exon 2 of 9	1	NM_001011719.2	ENSP00000370522.3

Frequencies

GnomAD3 genomes AF: 0.0000984 AC: 11 AN: 111762 Hom.: 0 Cov.: 22 AF XY: 0.0000884 AC XY: 3 AN XY: 33920

Gnomad AFR AF: 0.0000325

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000956

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000280

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000150

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000110 AC: 20 AN: 182353 Hom.: 0 AF XY: 0.000150 AC XY: 10 AN XY: 66871

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000145

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000221

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000179 AC: 196 AN: 1097555 Hom.: 0 Cov.: 30 AF XY: 0.000193 AC XY: 70 AN XY: 362933

Gnomad4 AFR exome AF: 0.0000379

Gnomad4 AMR exome AF: 0.0000284

Gnomad4 ASJ exome AF: 0.0000516

Gnomad4 EAS exome AF: 0.000132

Gnomad4 SAS exome AF: 0.0000370

Gnomad4 FIN exome AF: 0.0000247

Gnomad4 NFE exome AF: 0.000207

Gnomad4 OTH exome AF: 0.000195

GnomAD4 genome AF: 0.0000984 AC: 11 AN: 111816 Hom.: 0 Cov.: 22 AF XY: 0.0000883 AC XY: 3 AN XY: 33984

Gnomad4 AFR AF: 0.0000324

Gnomad4 AMR AF: 0.0000954

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000280

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000150

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000175 Hom.: 8

Bravo AF: 0.0000680

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000346 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000297 AC: 2

ExAC AF: 0.0000741 AC: 9

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Aug 16, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.196C>T (p.R66W) alteration is located in exon 2 (coding exon 2) of the ARSH gene. This alteration results from a C to T substitution at nucleotide position 196, causing the arginine (R) at amino acid position 66 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Benign:1

Mar 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ARSH: BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.47
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.65
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.73	D
FATHMM_MKL	Benign	0.41	N
LIST_S2	Pathogenic	0.97	D
M_CAP	Pathogenic	0.43	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.9	H
PrimateAI	Uncertain	0.59	T
PROVEAN	Pathogenic	-7.9	D
REVEL	Pathogenic	0.82
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.62
MVP		0.73
MPC		0.64
ClinPred		0.92	D
GERP RS		-2.4
Varity_R		0.86
gMVP		0.89

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

Publications

LitVar

Other links and lift over

dbSNP: rs148749736; hg19: chrX-2928174;