5-150297293-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

7
12

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]

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
ARSINM_001012301.4 linkuse as main transcriptc.1631G>A p.Arg544His missense_variant 2/2 ENST00000328668.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
ARSIENST00000328668.8 linkuse as main transcriptc.1631G>A p.Arg544His missense_variant 2/21 NM_001012301.4 P1Q5FYB1-1
ARSIENST00000515301.2 linkuse as main transcriptc.1202G>A p.Arg401His missense_variant 2/24 Q5FYB1-2

Frequencies

GnomAD3 genomes
AF:
0.000177
AC:
27
AN:
152144
Hom.:
0
Cov.:
32
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:
28
AN:
247722
Hom.:
0
AF XY:
0.0000971
AC XY:
13
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.:
1
Cov.:
29
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:
27
AN:
152144
Hom.:
0
Cov.:
32
AF XY:
0.000202
AC XY:
15
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.:
0
Bravo
AF:
0.000310
ExAC
AF:
0.0000906
AC:
11
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 submitterclinical testingAmbry GeneticsAug 03, 2022The 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 submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJul 12, 2023This 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
T
BayesDel_noAF
Uncertain
-0.020
CADD
Benign
21
DANN
Uncertain
1.0
DEOGEN2
Benign
0.25
T;.
Eigen
Benign
0.045
Eigen_PC
Benign
0.11
FATHMM_MKL
Uncertain
0.76
D
LIST_S2
Benign
0.73
T;T
M_CAP
Benign
0.077
D
MetaRNN
Benign
0.14
T;T
MetaSVM
Uncertain
0.46
D
MutationAssessor
Benign
0.34
N;.
MutationTaster
Benign
0.95
D;D
PrimateAI
Uncertain
0.67
T
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
T
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.

Other links and lift over

dbSNP: rs763136370; hg19: chr5-149676856; COSMIC: COSV60817209; COSMIC: COSV60817209; API