rs144340710
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PP3_Strong
The NM_000546.6(TP53):c.704A>T(p.Asn235Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,662 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N235S) has been classified as Likely benign.
Frequency
Consequence
NM_000546.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 30
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251484Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135912
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461662Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 727146
GnomAD4 genome Cov.: 30
ClinVar
Submissions by phenotype
Li-Fraumeni syndrome Uncertain:1
This sequence change replaces asparagine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 235 of the TP53 protein (p.Asn235Ile). This variant is present in population databases (no rsID available, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with TP53-related conditions. 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 expected to disrupt TP53 protein function with a positive predictive value of 95%. 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