rs121912667

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PM2PM5PP3_StrongPP5_Moderate

The NM_000546.6(TP53):c.854A>T(p.Glu285Val) variant causes a missense 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. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E285G) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

TP53
NM_000546.6 missense

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:3

Conservation

PhyloP100: 8.02

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]

TP53 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PM1

In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 7 benign, 16 uncertain in NM_000546.6

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr17-7673767-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 420133.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.988

PP5

Variant 17-7673766-T-A is Pathogenic according to our data. Variant chr17-7673766-T-A is described in ClinVar as [Pathogenic]. Clinvar id is 12384.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TP53	NM_000546.6 linkuse as main transcript	c.854A>T	p.Glu285Val	missense_variant	8/11	ENST00000269305.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TP53	ENST00000269305.9 linkuse as main transcript	c.854A>T	p.Glu285Val	missense_variant	8/11	1	NM_000546.6	P1	P04637-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1461892

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727246

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Li-Fraumeni syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 21, 2018

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the¬†p.Glu285¬†amino acid residue in TP53. Other variant(s) that disrupt this residue have been observed in individuals with TP53-related conditions (PMID:¬†11051239,¬†22507745, 23894400), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. This variant has been reported to affect TP53 protein function (PMID: 12826609, 18762572, 25584008). This variant has been observed to be de novo in an individual affected with¬†pediatric adrenocortical carcinoma and choroid plexus carcinoma¬†(PMID: 18762572,¬†25584008). ClinVar contains an entry for this variant (Variation ID: 12384). This variant is present in population databases (rs121912667, ExAC 0.002%). This sequence change replaces glutamic acid with valine at codon 285 of the TP53 protein (p.Glu285Val). The glutamic acid residue is highly conserved and there is a moderate physicochemical difference between glutamic acid and valine. -

Adrenocortical carcinoma, pediatric

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 01, 2008

- -

Choroid plexus carcinoma

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 01, 2008

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.48

BayesDel_noAF

Pathogenic

0.45

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.83

D;.;.;.;.;T;T;.;D;.;.;.;.;.;.;D;.;.;.

Eigen

Pathogenic

0.73

Eigen_PC

Uncertain

0.66

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.93

D;D;D;D;D;D;D;.;.;.;D;D;.;D;D;D;D;D;D

M_CAP

Pathogenic

0.81

MetaRNN

Pathogenic

0.99

D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Pathogenic

0.96

MutationAssessor

Uncertain

2.7

.;.;.;.;.;.;.;.;M;.;M;M;M;.;.;M;.;.;.

MutationTaster

Benign

1.0

A;A;A;A;A;A

PrimateAI

Benign

0.38

PROVEAN

Pathogenic

-5.7

D;.;.;.;.;.;.;.;D;.;.;D;D;.;.;D;.;.;D

REVEL

Pathogenic

0.94

Sift

Pathogenic

0.0

D;.;.;.;.;.;.;.;D;.;.;D;D;.;.;D;.;.;D

Sift4G

Pathogenic

0.0010

D;T;T;D;D;T;T;D;D;D;D;D;D;D;D;D;D;D;T

Polyphen

1.0, 0.99

.;.;.;.;.;.;.;.;D;.;D;D;D;.;.;D;.;.;.

Vest4

0.71

MutPred

0.89

Gain of MoRF binding (P = 0.0173);.;.;.;.;.;.;.;Gain of MoRF binding (P = 0.0173);.;Gain of MoRF binding (P = 0.0173);Gain of MoRF binding (P = 0.0173);Gain of MoRF binding (P = 0.0173);.;.;Gain of MoRF binding (P = 0.0173);.;.;.;

MVP

0.97

MPC

0.40

ClinPred

1.0

GERP RS

5.0

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

3.7

Varity_R

0.95

gMVP

0.82

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over