rs121917718
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PP3_StrongBS2
The NM_001366110.1(PAX4):c.514C>T(p.Arg172Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000242 in 1,613,916 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 Uncertain significance (★★).
Frequency
Consequence
NM_001366110.1 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
PAX4 | ENST00000639438.3 | c.514C>T | p.Arg172Trp | missense_variant | Exon 7 of 12 | 5 | NM_001366110.1 | ENSP00000491782.1 |
Frequencies
GnomAD3 genomes AF: 0.0000329 AC: 5AN: 152038Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.0000517 AC: 13AN: 251454Hom.: 0 AF XY: 0.0000589 AC XY: 8AN XY: 135898
GnomAD4 exome AF: 0.0000233 AC: 34AN: 1461878Hom.: 0 Cov.: 33 AF XY: 0.0000248 AC XY: 18AN XY: 727240
GnomAD4 genome AF: 0.0000329 AC: 5AN: 152038Hom.: 0 Cov.: 31 AF XY: 0.0000539 AC XY: 4AN XY: 74256
ClinVar
Submissions by phenotype
Maturity-onset diabetes of the young type 9 Pathogenic:1Uncertain:1
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Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. Following criteria are met: 0105 - The mechanism of disease for this gene is not clearly established. Loss of function has been suggested as the mechanism of disease, but dominant negative has not been excluded (PMID: 17426099). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to tryptophan. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (14 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (12 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated homeodomain (PMID: 17426099). (I) 0704 - Another missense variant comparable to the one identified in this case has limited previous evidence for pathogenicity. p.(Arg164Gln) has been observed as heterozygous in several members of a large family with type 2 diabetes mellitus or impaired glucose tolerance (PMID: 32801813). This variant has also been classified as a VUS by two clinical laboratoies in ClinVar and in the literature (PMID: 34135026). (SP) 0803 - This variant has limited previous evidence of pathogenicity in an unrelated individual. This variant has been observed in three members of one family with type 2 diabetes mellitus and one member with impaired glucose tolerance, but was not observed in two other members of this family who also had impaired glucose tolerance (PMID: 17426099) (SP) 0906 - Segregation evidence for this variant is inconclusive. This variant has been observed in three members of one family with type 2 diabetes mellitus and 1 member with impaired glucose tolerance, but was not observed in another two family members with impaired glucose tolerance (PMID: 32801813). (I) 1002 - This variant has moderate functional evidence supporting abnormal protein function. This variant has been shown to reduce the repression of insulin activity compared to WT cells (PMID: 17426099). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
not provided Uncertain:2
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. This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 164 of the PAX4 protein (p.Arg164Trp). This variant is present in population databases (rs121917718, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features of maturity-onset diabetes of the young (PMID: 17426099). ClinVar contains an entry for this variant (Variation ID: 13793). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects PAX4 function (PMID: 17426099, 25951767). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. -
PAX4: PM2:Supporting, PP1, PS3:Supporting -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at