Variant 17-7673593-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1PM2BP4

The NM_000546.6(TP53):c.935C>T(p.Thr312Ile) 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 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. T312S) has been classified as Benign.

Frequency

Genomes: not found (cov: 31)

Consequence

TP53
NM_000546.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.29

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 Uncertain_significance. Variant got 3 ACMG points.

PM1

In a region_of_interest Interaction with HIPK1 (size 270) in uniprot entity P53_HUMAN there are 516 pathogenic changes around while only 128 benign (80%) in NM_000546.6

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.30912882).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TP53	NM_000546.6 linkuse as main transcript	c.935C>T	p.Thr312Ile	missense_variant	9/11	ENST00000269305.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TP53	ENST00000269305.9 linkuse as main transcript	c.935C>T	p.Thr312Ile	missense_variant	9/11	1	NM_000546.6	P1	P04637-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Aug 15, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Pathogenic

0.21

BayesDel_noAF

Uncertain

0.070

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.023

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

Eigen

Benign

0.13

Eigen_PC

Benign

0.094

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.95

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

M_CAP

Uncertain

0.22

MetaRNN

Benign

0.31

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

MetaSVM

Pathogenic

1.0

MutationAssessor

Uncertain

2.1

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

MutationTaster

Benign

1.0

D;N;N;N;N;N

PrimateAI

Benign

0.40

PROVEAN

Benign

-2.1

N;.;.;.;.;.;.;.;N;.;.;N;N;.;.;N;.;.;N

REVEL

Uncertain

0.52

Sift

Uncertain

0.020

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

Sift4G

Benign

0.088

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

Polyphen

0.15, 0.71, 0.63

.;.;.;.;.;.;.;.;B;.;P;P;P;.;.;B;.;.;.

Vest4

0.30

MutPred

0.24

Loss of glycosylation at T312 (P = 0.0102);.;.;.;.;.;.;.;Loss of glycosylation at T312 (P = 0.0102);.;Loss of glycosylation at T312 (P = 0.0102);Loss of glycosylation at T312 (P = 0.0102);Loss of glycosylation at T312 (P = 0.0102);.;.;Loss of glycosylation at T312 (P = 0.0102);.;.;.;

MVP

0.90

MPC

0.22

ClinPred

0.66

GERP RS

5.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.12

gMVP

0.50

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over