ENST00000504937.5:c.1A>G

Variant names:

• chr17-7675215-T-C
• rs1057280220
• ENST00000504937.5:c.1A>G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PM2

The ENST00000504937.5(TP53):​c.1A>G​(p.Met1?) variant causes a start lost 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: TP53 ENST00000504937.5 start_lost
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.47

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]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 90 pathogenic variants. Next in-frame start position is after 28 codons. Genomic position: 7675134. Lost 0.104 part of the original CDS.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TP53	NM_000546.6	c.397A>G	p.Met133Val	missense_variant	Exon 5 of 11	ENST00000269305.9	NP_000537.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TP53	ENST00000269305.9	c.397A>G	p.Met133Val	missense_variant	Exon 5 of 11	1	NM_000546.6	ENSP00000269305.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250826 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135576

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000884

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Li-Fraumeni syndrome Uncertain:1

Jul 01, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 133 of the TP53 protein (p.Met133Val). This variant is present in population databases (no rsID available, gnomAD 0.0009%). 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: 528246). 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 with a negative predictive value of 97.5%. Experimental studies have shown that this missense change does not substantially affect TP53 function (PMID: 12826609). This variant disrupts the p.Met133 amino acid residue in TP53. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1933902, 12826609, 17606709, 20128691, 21343334). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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	0.21
BayesDel_addAF	Pathogenic	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Benign	20
DANN	Benign	0.96
DEOGEN2	Benign	0.40	T;T;.;.;.;.;D;.;.;.;.;.;.;D;.;.;.;T;T;T
Eigen	Benign	-0.75
Eigen_PC	Benign	-0.56
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.89	D;D;D;D;D;.;.;.;D;D;.;D;D;D;D;T;D;D;D;T
M_CAP	Uncertain	0.27	D
MetaRNN	Uncertain	0.59	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.66	D
MutationAssessor	Benign	-0.69	.;.;.;.;.;.;N;.;N;N;N;.;.;N;.;.;.;.;.;.
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-1.0	N;N;.;.;.;.;N;.;.;N;N;.;.;N;.;.;N;N;N;.
REVEL	Uncertain	0.50
Sift	Uncertain	0.028	D;D;.;.;.;.;D;.;.;D;D;.;.;D;.;.;D;D;D;.
Sift4G	Uncertain	0.033	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;.;.;D
Polyphen		0.041	B;.;.;.;.;.;B;.;B;B;B;.;.;B;.;.;.;B;.;.
Vest4		0.39
MutPred		0.82		Loss of catalytic residue at M133 (P = 9e-04);Loss of catalytic residue at M133 (P = 9e-04);.;.;.;.;Loss of catalytic residue at M133 (P = 9e-04);.;Loss of catalytic residue at M133 (P = 9e-04);Loss of catalytic residue at M133 (P = 9e-04);Loss of catalytic residue at M133 (P = 9e-04);.;.;Loss of catalytic residue at M133 (P = 9e-04);.;.;.;.;Loss of catalytic residue at M133 (P = 9e-04);.;
MVP		0.91
MPC		0.67
ClinPred		0.19	T
GERP RS		-0.051
Varity_R		0.46
gMVP		0.30

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

Other links and lift over

dbSNP: rs1057280220; hg19: chr17-7578533; COSMIC: COSV53106978; COSMIC: COSV53106978;