chr3-189958001-G-A
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PVS1_ModeratePM2
The NM_018192.4(P3H2):c.2038C>T(p.Arg680*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000124 in 1,611,038 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_018192.4 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
P3H2 | ENST00000319332.10 | c.2038C>T | p.Arg680* | stop_gained | Exon 15 of 15 | 1 | NM_018192.4 | ENSP00000316881.5 | ||
P3H2 | ENST00000427335.6 | c.1495C>T | p.Arg499* | stop_gained | Exon 15 of 15 | 1 | ENSP00000408947.2 | |||
P3H2 | ENST00000490940.1 | n.168C>T | non_coding_transcript_exon_variant | Exon 2 of 2 | 2 |
Frequencies
GnomAD3 genomes AF: 0.0000132 AC: 2AN: 151914Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.0000279 AC: 7AN: 250470Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135494
GnomAD4 exome AF: 0.0000123 AC: 18AN: 1459124Hom.: 0 Cov.: 29 AF XY: 0.0000138 AC XY: 10AN XY: 726110
GnomAD4 genome AF: 0.0000132 AC: 2AN: 151914Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 74174
ClinVar
Submissions by phenotype
P3H2-related disorder Uncertain:1
The P3H2 c.2038C>T variant is predicted to result in premature protein termination (p.Arg680*). To our knowledge, this variant has not been reported in the literature. While other nonsense and frameshift variants in P3H2 have been reported in individuals with myopia and/or cataracts (Guo et al. 2014. PubMed ID: 24172257; Khan et al. 2019. PubMed ID: 30608193), none have been reported downstream of this variant. Additionally, this variant is located in the terminal exon and therefore the transcript is not expected to undergo nonsense mediated decay. This variant is reported in 0.016% of alleles in individuals of South Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/3-189675790-G-A). Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -
not provided Uncertain:1
This sequence change creates a premature translational stop signal (p.Arg680*) in the P3H2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 29 amino acid(s) of the P3H2 protein. This variant is present in population databases (rs751877902, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with P3H2-related conditions. ClinVar contains an entry for this variant (Variation ID: 844528). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at