rs1554251356
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_ModeratePM2PP5_Very_Strong
The NM_000045.4(ARG1):c.938del(p.Lys313SerfsTer22) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000031 in 1,614,006 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000027 ( 0 hom. )
Consequence
ARG1
NM_000045.4 frameshift
NM_000045.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 0.597
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]
MED23 (HGNC:2372): (mediator complex subunit 23) The activation of gene transcription is a multistep process that is triggered by factors that recognize transcriptional enhancer sites in DNA. These factors work with co-activators to direct transcriptional initiation by the RNA polymerase II apparatus. The protein encoded by this gene is a subunit of the CRSP (cofactor required for SP1 activation) complex, which, along with TFIID, is required for efficient activation by SP1. This protein is also a component of other multisubunit complexes e.g. thyroid hormone receptor-(TR-) associated proteins which interact with TR and facilitate TR function on DNA templates in conjunction with initiation factors and cofactors. This protein also acts as a metastasis suppressor. Several alternatively spliced transcript variants encoding different isoforms have been described for this gene. [provided by RefSeq, Jul 2012]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 12 ACMG points.
PVS1
?
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.033 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 6-131583875-CA-C is Pathogenic according to our data. Variant chr6-131583875-CA-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 459925.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ARG1 | NM_000045.4 | c.938del | p.Lys313SerfsTer22 | frameshift_variant | 8/8 | ENST00000368087.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ARG1 | ENST00000368087.8 | c.938del | p.Lys313SerfsTer22 | frameshift_variant | 8/8 | 1 | NM_000045.4 | P3 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152190Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251050Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135676
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GnomAD4 exome AF: 0.00000274 AC: 4AN: 1461816Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 727206
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Arginase deficiency Pathogenic:3
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 31, 2022 | Variant summary: ARG1 c.938delA (p.Lys313SerfsX22) causes a frameshift which results in an extension of the protein. The variant allele was found at a frequency of 1.6e-05 in 251050 control chromosomes. c.938delA has been reported in the literature in settings of exome sequencing in newborn screening for inborn errors of metabolism, however the exact clinical details, genotype, zygosity are not specified (example, Adhikari_2020). These report(s) do not provide unequivocal conclusions about association of the variant with Arginase Deficiency. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Aug 09, 2023 | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 459925). This frameshift has been observed in individual(s) with arginase deficiency (Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is present in population databases (no rsID available, gnomAD 0.01%). This sequence change results in a frameshift in the ARG1 gene (p.Lys313Serfs*22). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 10 amino acid(s) of the ARG1 protein and extend the protein by 11 additional amino acid residues. - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Sep 09, 2023 | - - |
Computational scores
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at