NM_000546.6:c.672+2T>A
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_000546.6(TP53):c.672+2T>A variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★).
Frequency
Consequence
NM_000546.6 splice_donor, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 exome Cov.: 34
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Li-Fraumeni syndrome Pathogenic:1
The c.672+2T>A variant in TP53 has not been previously reported in individuals w ith Li-Fraumeni syndrome and was absent from large population studies. This vari ant occurs in the invariant region (+/- 1,2) of the splice consensus sequence an d is predicted to cause altered splicing leading to an abnormal or absent protei n. Loss of function of the TP53 gene is an established disease mechanism for Li Fraumeni syndrome. Three other variants at this splice site have been reported i n individuals with Li-Fraumeni syndrome, two of them affecting the same nucleoti de (Wong 2003, Gonzalez 2009) and two affecting the +1 position (Sakurai 2103, A chatz 2017), further supporting a pathogenic role of the c.672+2T>A variant. In summary, although additional studies are required to fully establish its clinica l significance, the c.672+2T>A variant is likely pathogenic. -
not provided Other:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at