rs28941474
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong
The NM_000045.4(ARG1):āc.32T>Cā(p.Ile11Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000031 in 1,613,948 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (ā ā ).
Frequency
Genomes: š 0.0000066 ( 0 hom., cov: 32)
Exomes š: 0.0000027 ( 0 hom. )
Consequence
ARG1
NM_000045.4 missense
NM_000045.4 missense
Scores
6
12
1
Clinical Significance
Conservation
PhyloP100: 5.62
Genes affected
ARG1 (HGNC:663): (arginase 1) Arginase catalyzes the hydrolysis of arginine to ornithine and urea. At least two isoforms of mammalian arginase exist (types I and II) which differ in their tissue distribution, subcellular localization, immunologic crossreactivity and physiologic function. The type I isoform encoded by this gene, is a cytosolic enzyme and expressed predominantly in the liver as a component of the urea cycle. Inherited deficiency of this enzyme results in argininemia, an autosomal recessive disorder characterized by hyperammonemia. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2011]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 14 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.984
PP5
?
Variant 6-131573314-T-C is Pathogenic according to our data. Variant chr6-131573314-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2393.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-131573314-T-C is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ARG1 | NM_000045.4 | c.32T>C | p.Ile11Thr | missense_variant | 1/8 | ENST00000368087.8 | |
ARG1 | NM_001244438.2 | c.32T>C | p.Ile11Thr | missense_variant | 1/8 | ||
ARG1 | NM_001369020.1 | c.32T>C | p.Ile11Thr | missense_variant | 1/6 | ||
ARG1 | NR_160934.1 | n.89T>C | non_coding_transcript_exon_variant | 1/7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ARG1 | ENST00000368087.8 | c.32T>C | p.Ile11Thr | missense_variant | 1/8 | 1 | NM_000045.4 | P3 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152118Hom.: 0 Cov.: 32
GnomAD3 genomes
?
AF:
AC:
1
AN:
152118
Hom.:
Cov.:
32
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD3 exomes AF: 0.00000399 AC: 1AN: 250904Hom.: 0 AF XY: 0.00000738 AC XY: 1AN XY: 135580
GnomAD3 exomes
AF:
AC:
1
AN:
250904
Hom.:
AF XY:
AC XY:
1
AN XY:
135580
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.00000274 AC: 4AN: 1461830Hom.: 0 Cov.: 30 AF XY: 0.00000413 AC XY: 3AN XY: 727222
GnomAD4 exome
AF:
AC:
4
AN:
1461830
Hom.:
Cov.:
30
AF XY:
AC XY:
3
AN XY:
727222
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152118Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74302
GnomAD4 genome
?
AF:
AC:
1
AN:
152118
Hom.:
Cov.:
32
AF XY:
AC XY:
1
AN XY:
74302
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
ExAC
?
AF:
AC:
1
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Arginase deficiency Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 03, 2024 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Sep 01, 1995 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 19, 2022 | For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt ARG1 protein function. ClinVar contains an entry for this variant (Variation ID: 2393). This missense change has been observed in individual(s) with argininemia (PMID: 7649538, 21310339, 22959135, 26310552, 29443755). This variant is present in population databases (rs28941474, gnomAD 0.003%). This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 11 of the ARG1 protein (p.Ile11Thr). - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Lifecell International Pvt. Ltd | - | A Homozygote Missense variant c.32T>C in Exon 1 of the ARG1 gene that results in the amino acid substitution p.Ile11Thr was identified. The observed variant is novel in gnomAD exomes and genomes. The severity of the impact of this variant on the protein is medium, based on the effect of the protein and REVEL score. Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as Pathogenic [Variation ID: 2393]. The observed variation has been previously reported in patients affected with hyperargininemia (Carvalho, Daniel Rocha et al., 2012). For these reasons, this variant has been classified as Likely Pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Pathogenic
D;.;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Pathogenic
M;M;M
MutationTaster
Benign
A;A;A
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D;.
REVEL
Pathogenic
Sift
Uncertain
D;D;.
Sift4G
Uncertain
D;D;.
Polyphen
D;D;.
Vest4
MutPred
Gain of glycosylation at I11 (P = 0.0218);Gain of glycosylation at I11 (P = 0.0218);Gain of glycosylation at I11 (P = 0.0218);
MVP
MPC
0.42
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at