rs35155575
Variant summary
Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP3BP4_StrongBP6BS2
The NM_001366110.1(PAX4):c.133C>T(p.Arg45Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000269 in 1,614,168 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R45Q) has been classified as Uncertain significance.
Frequency
Consequence
NM_001366110.1 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PAX4 | NM_001366110.1 | c.133C>T | p.Arg45Trp | missense_variant | 4/12 | ENST00000639438.3 | |
PAX4 | NM_001366111.1 | c.133C>T | p.Arg45Trp | missense_variant | 2/10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PAX4 | ENST00000639438.3 | c.133C>T | p.Arg45Trp | missense_variant | 4/12 | 5 | NM_001366110.1 | A2 |
Frequencies
GnomAD3 genomes ? AF: 0.00135 AC: 206AN: 152184Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000427 AC: 107AN: 250682Hom.: 1 AF XY: 0.000302 AC XY: 41AN XY: 135572
GnomAD4 exome AF: 0.000155 AC: 226AN: 1461866Hom.: 3 Cov.: 69 AF XY: 0.000142 AC XY: 103AN XY: 727232
GnomAD4 genome ? AF: 0.00137 AC: 209AN: 152302Hom.: 1 Cov.: 32 AF XY: 0.00124 AC XY: 92AN XY: 74486
ClinVar
Submissions by phenotype
not provided Uncertain:2Benign:1
Uncertain significance, flagged submission | clinical testing | Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital | Dec 17, 2019 | The p.Arg37Trp variant is predicted to substitute the arginine at position 37 with a tryptophan and the majority of in silico tools predict this variant has a damaging effect. This variant was reported as a heterozygous change in a single individual with ketosis-prone diabetes and was demonstrated to have reduced function in in vitro assays (PMID: 15509590). This variant is found in individuals with African ancestry with an allele frequency of 0.5% (~1/100 are carriers; 1 individual with homozygous change) in the Genome Aggregation Database. - |
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 25, 2024 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Aug 23, 2021 | Published functional studies suggest a damaging effect, specifically in vitro analyses illustrate a reduction in the PAX4-binding ability to target gene promoters (Mauvais-Jarvis et al., 2004); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32801813, 15509590, 20981092) - |
not specified Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 20, 2022 | - - |
Benign, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Jul 31, 2018 | - - |
Type 2 diabetes mellitus;C2677132:Maturity-onset diabetes of the young type 9 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | New York Genome Center | Dec 02, 2021 | The heterozygous missense variant c.133C>T (p.Arg45Trp) identified in exon 4 (of 12) of the PAX4 gene has been reported in a patient with Ketosis-prone diabetes (KPD), a rare form of type 2 diabetes, mostly observed in subjects of west Africans and African-Americans (PMID: 15509590). The variant has 0.004851 allele frequency in the African/African American subpopulation represented in the gnomAD(v3.1.2) database (201 heterozygous alleles. Additionally, one homozygous allele in the gnomADv2.1.1 database). This variant is reported as a Variant of Uncertain Significance and benign in the ClinVar database (Variation ID:13792). The variant affects a conserved residue (Arg45) located in the paired box domain of PAX4 gene (PMID: 15509590) and is predicted deleterious by multiple insilico prediction tools (CADD score = 27.9, REVEL score = 0.917). In vitro functional analyses of c.133C>T (p.Arg45Trp) suggested impaired PAX4-binding ability to target gene promoters (PMID: 15509590). Based on the available evidence, the c.133C>T (p.Arg45Trp) variant identified in the PAX4 gene is reported as a Variant of Uncertain Significance. - |
Hyperglycemia Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital | - | The p.Arg45Trp variant is predicted to substitute the arginine at position 45 with a tryptophan and the majority of in silico tools predict this variant has a damaging effect. This variant was reported as a heterozygous change in a single individual with ketosis-prone diabetes and was demonstrated to have reduced function in in vitro assays (PMID: 15509590). This variant is found in individuals with African ancestry with an allele frequency of 0.5% (~1/100 are carriers; 1 individual with homozygous change) in the Genome Aggregation Database. - |
Diabetes mellitus, ketosis-prone, susceptibility to Other:1
risk factor, no assertion criteria provided | literature only | OMIM | Dec 15, 2004 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at