rs1057519987

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PS1_ModeratePM1PM2PM5PP3_ModeratePP5

The NM_000546.6(TP53):c.810T>G(p.Phe270Leu) variant causes a missense change involving the alteration of a non-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 Likely pathogenic (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F270C) has been classified as Likely pathogenic.

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

Likely pathogenic no assertion criteria provided P:9

Conservation

PhyloP100: 0.128

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

PS1

Transcript NM_000546.6 (TP53) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 1431729

PM1

In a hotspot region, there are 13 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 17 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 chr17-7673811-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 376594.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.893

PP5

Variant 17-7673810-A-C is Pathogenic according to our data. Variant chr17-7673810-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 376595.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TP53	NM_000546.6 linkuse as main transcript	c.810T>G	p.Phe270Leu	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.810T>G	p.Phe270Leu	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:

1461740

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727178

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.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:9

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Carcinoma of esophagus

Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Squamous cell carcinoma of the skin

Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Gastric adenocarcinoma

Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Squamous cell lung carcinoma

Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Breast neoplasm

Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Lung adenocarcinoma

Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Neoplasm of brain

Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Ovarian serous cystadenocarcinoma

Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Squamous cell carcinoma of the head and neck

Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.42

BayesDel_noAF

Pathogenic

0.36

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.66

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

Eigen

Benign

0.071

Eigen_PC

Benign

0.037

FATHMM_MKL

Uncertain

0.92

LIST_S2

Pathogenic

0.98

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

M_CAP

Pathogenic

0.79

MetaRNN

Pathogenic

0.89

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

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.1

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

MutationTaster

Benign

1.0

D;D;D;D;D;D

PrimateAI

Uncertain

0.72

PROVEAN

Pathogenic

-5.3

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

REVEL

Pathogenic

0.83

Sift

Benign

0.064

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

Sift4G

Benign

0.083

T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T

Polyphen

1.0, 0.16

.;.;.;.;.;.;.;.;D;.;D;B;D;.;.;D;.;.;.

Vest4

0.93

MutPred

0.73

Loss of catalytic residue at F270 (P = 0.0443);.;.;.;.;.;.;.;Loss of catalytic residue at F270 (P = 0.0443);.;Loss of catalytic residue at F270 (P = 0.0443);Loss of catalytic residue at F270 (P = 0.0443);Loss of catalytic residue at F270 (P = 0.0443);.;.;Loss of catalytic residue at F270 (P = 0.0443);.;.;.;

MVP

0.97

MPC

0.40

ClinPred

0.99

GERP RS

2.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.94

gMVP

0.58

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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