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rs1042522

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM5BP4_Moderate

The NM_000546.6(TP53):c.215C>T(p.Pro72Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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)
Exomes 𝑓: 6.8e-7 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

TP53
NM_000546.6 missense

Scores

1
4
13

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.44
Variant links:
Genes affected
TP53 (HGNC:11998): (tumor protein p53) This gene encodes a tumor suppressor protein containing transcriptional activation, DNA binding, and oligomerization domains. The encoded protein responds to diverse cellular stresses to regulate expression of target genes, thereby inducing cell cycle arrest, apoptosis, senescence, DNA repair, or changes in metabolism. Mutations in this gene are associated with a variety of human cancers, including hereditary cancers such as Li-Fraumeni syndrome. Alternative splicing of this gene and the use of alternate promoters result in multiple transcript variants and isoforms. Additional isoforms have also been shown to result from the use of alternate translation initiation codons from identical transcript variants (PMIDs: 12032546, 20937277). [provided by RefSeq, Dec 2016]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance.

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
GnomAD4 exome
Data not reliable, filtered out with message: AS_VQSR
AF:
6.84e-7
AC:
1
AN:
1461570
Hom.:
0
Cov.:
80
AF XY:
0.00000138
AC XY:
1
AN XY:
727076
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
8.99e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
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 testingInvitaeJan 02, 2023In 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. Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 12826609, 29979965, 30224644) indicates that this missense variant is not expected to disrupt TP53 function. ClinVar contains an entry for this variant (Variation ID: 864652). This variant has not been reported in the literature in individuals affected with TP53-related conditions. This variant is not present in population databases (gnomAD no frequency). This 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). -

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
13
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; API