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rs1042522

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2_SupportingPM5BP4_Moderate

The NM_000546.6(TP53):c.215C>T(p.Pro72Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD Genomes project. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign 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. P72A) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)

Consequence

TP53
NM_000546.6 missense

Scores

1
4
13

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.44

Links

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2
?
Very rare variant; Number of alleles below threshold, Median coverage is 31.
PM5
?
Other missense variant is known to change same aminoacid residue: Variant chr17-7676154-G-C is described in Lovd as [Pathogenic].
BP4
?
Computational evidence support a benign effect (MetaRNN=0.16614896).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
TP53NM_000546.6 linkuse as main transcriptc.215C>T p.Pro72Leu missense_variant 4/11 ENST00000269305.9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
TP53ENST00000269305.9 linkuse as main transcriptc.215C>T p.Pro72Leu missense_variant 4/111 NM_000546.6 P1P04637-1

Frequencies

GnomAD3 genomes
Cov.:
31

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Li-Fraumeni syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingInvitaeSep 01, 2022This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 72 of the TP53 protein (p.Pro72Leu). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with TP53-related conditions. ClinVar contains an entry for this variant (Variation ID: 864652). Advanced modeling of experimental studies (such as gene expression, population dynamics, functional pathways, and cell-cycle effects in cell culture) performed at Invitae indicates that this missense variant is not expected to disrupt TP53 protein function. 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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.080
BayesDel_addAF
Uncertain
0.087
D
BayesDel_noAF
Benign
-0.11
Cadd
Benign
6.1
Dann
Benign
0.55
DEOGEN2
Benign
0.018
T;T;.;T;.;.;.;.;.;.;T;.;.;T;T;.
Eigen
Benign
-0.93
Eigen_PC
Benign
-0.98
FATHMM_MKL
Benign
0.33
N
LIST_S2
Uncertain
0.87
D;D;.;.;.;D;D;.;D;D;D;D;D;D;D;D
M_CAP
Uncertain
0.18
D
MetaRNN
Benign
0.17
T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM
Pathogenic
0.86
D
MutationTaster
Benign
1.0
N;N;N;N;N;N
PrimateAI
Benign
0.40
T
PROVEAN
Benign
-0.66
N;N;.;N;.;.;N;N;.;.;N;.;.;N;.;N
REVEL
Uncertain
0.34
Sift
Benign
0.087
T;T;.;T;.;.;T;D;.;.;T;.;.;T;.;T
Sift4G
Benign
0.48
T;T;T;T;T;T;T;T;T;T;T;T;T;.;T;.
Polyphen
0.29
B;.;.;B;.;B;B;B;.;.;B;.;.;B;.;.
Vest4
0.25
MutPred
0.26
Gain of stability (P = 0.0106);Gain of stability (P = 0.0106);.;Gain of stability (P = 0.0106);.;Gain of stability (P = 0.0106);Gain of stability (P = 0.0106);Gain of stability (P = 0.0106);.;.;Gain of stability (P = 0.0106);.;Gain of stability (P = 0.0106);Gain of stability (P = 0.0106);Gain of stability (P = 0.0106);Gain of stability (P = 0.0106);
MVP
0.89
MPC
0.69
ClinPred
0.045
T
GERP RS
1.9
Varity_R
0.073
gMVP
0.23

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1042522; hg19: chr17-7579472;