5-150297293-C-T

Position:

chr5-150297293-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001012301.4(ARSI):c.1631G>A(p.Arg544His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000299 in 1,609,840 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00018 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00031 ( 1 hom. )

Consequence

ARSI
NM_001012301.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 1.11

Variant links:

Genes affected

ARSI (HGNC:32521): (arylsulfatase family member I) This gene encodes a protein that belongs to a large family of sulfatases that hydrolyze sulfate esters and sulfamates. Members of this family play a role in several cellular processes, including hormone synthesis, cell signaling in development and degradation of macromolecules. The protein encoded by this gene is thought to be secreted, and to function in extracellular space. [provided by RefSeq, Jul 2016]

ARSI links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.14260128).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARSI	NM_001012301.4 linkuse as main transcript	c.1631G>A	p.Arg544His	missense_variant	2/2	ENST00000328668.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARSI	ENST00000328668.8 linkuse as main transcript	c.1631G>A	p.Arg544His	missense_variant	2/2	1	NM_001012301.4	P1	Q5FYB1-1
ARSI	ENST00000515301.2 linkuse as main transcript	c.1202G>A	p.Arg401His	missense_variant	2/2	4			Q5FYB1-2

Frequencies

GnomAD3 genomes

AF:

0.000177

AC:

AN:

152144

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000654

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:

0.000206

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000113

AC:

AN:

247722

Hom.:

AF XY:

0.0000971

AC XY:

AN XY:

133918

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000238

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000169

Gnomad OTH exome

AF:

0.000166

GnomAD4 exome

AF:

0.000311

AC:

454

AN:

1457696

Hom.:

Cov.:

AF XY:

0.000284

AC XY:

206

AN XY:

725122

show subpopulations

Gnomad4 AFR exome

AF:

0.0000602

Gnomad4 AMR exome

AF:

0.000298

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000234

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000382

Gnomad4 OTH exome

AF:

0.000216

GnomAD4 genome

AF:

0.000177

AC:

AN:

152144

Hom.:

Cov.:

AF XY:

0.000202

AC XY:

AN XY:

74334

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000206

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.000407

Hom.:

Bravo

AF:

0.000310

ExAC

AF:

0.0000906

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.000237

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 03, 2022

The c.1631G>A (p.R544H) alteration is located in exon 2 (coding exon 2) of the ARSI gene. This alteration results from a G to A substitution at nucleotide position 1631, causing the arginine (R) at amino acid position 544 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Spastic paraplegia

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jul 12, 2023

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 544 of the ARSI protein (p.Arg544His). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The histidine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. ClinVar contains an entry for this variant (Variation ID: 661582). This variant has not been reported in the literature in individuals affected with ARSI-related conditions. This variant is present in population databases (rs763136370, gnomAD 0.02%). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.055

BayesDel_noAF

Uncertain

-0.020

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.25

T;.

Eigen

Benign

0.045

Eigen_PC

Benign

0.11

FATHMM_MKL

Uncertain

0.76

LIST_S2

Benign

0.73

T;T

M_CAP

Benign

0.077

MetaRNN

Benign

0.14

T;T

MetaSVM

Uncertain

0.46

MutationAssessor

Benign

0.34

N;.

MutationTaster

Benign

0.95

D;D

PrimateAI

Uncertain

0.67

PROVEAN

Benign

-0.48

N;N

REVEL

Uncertain

0.42

Sift

Benign

0.066

T;T

Sift4G

Uncertain

0.027

D;D

Polyphen

0.80

P;.

Vest4

0.18

MutPred

0.21

Loss of MoRF binding (P = 0.0867);.;

MVP

0.92

MPC

0.40

ClinPred

0.050

GERP RS

3.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.042

gMVP

0.56

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over