17-7675226-G-C

Position:

• chr17-7675226-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_000546.6(TP53):​c.386C>G​(p.Ala129Gly) 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. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: TP53 NM_000546.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -2.58

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 Uncertain_significance. Variant got 2 ACMG points.

• PM1: In a region_of_interest Interaction with AXIN1 (size 176) in uniprot entity P53_HUMAN there are 53 pathogenic changes around while only 3 benign (95%) in NM_000546.6
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20093167).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TP53	NM_000546.6	c.386C>G	p.Ala129Gly	missense_variant	5/11	ENST00000269305.9	NP_000537.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TP53	ENST00000269305.9	c.386C>G	p.Ala129Gly	missense_variant	5/11	1	NM_000546.6	ENSP00000269305.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Li-Fraumeni syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 13, 2017

This sequence change replaces alanine with glycine at codon 129 of the TP53 protein (p.Ala129Gly). The alanine residue is weakly conserved and there is a small physicochemical difference between alanine and glycine. In summary, this variant is a rare missense change that has been shown not to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance. An experimental study using yeast-based functional assays has shown that this missense change does not significantly affect the transcriptional transactivation activity of the TP53 protein (PMID: 12826609). This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a TP53-related disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Uncertain	0.065	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	3.6
DANN	Benign	0.63
DEOGEN2	Uncertain	0.50	T;T;.;D;.;.;.;.;.;.;D;.;.;T;T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.68	T;T;.;.;.;T;T;.;T;T;T;T;T;T;T
M_CAP	Pathogenic	0.29	D
MetaRNN	Benign	0.20	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Benign	-0.34	.;.;.;N;.;N;N;N;.;.;N;.;.;.;.
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-1.5	N;N;.;N;.;.;N;N;.;.;N;.;.;N;N
REVEL	Uncertain	0.41
Sift	Benign	0.37	T;T;.;T;.;.;T;T;.;.;T;.;.;T;T
Sift4G	Benign	0.38	T;T;T;T;T;T;T;T;T;T;T;T;T;.;.
Polyphen		0.0	B;.;.;B;.;B;B;B;.;.;B;.;.;B;.
Vest4		0.15
MutPred		0.33		Gain of methylation at K132 (P = 0.0963);Gain of methylation at K132 (P = 0.0963);.;Gain of methylation at K132 (P = 0.0963);.;Gain of methylation at K132 (P = 0.0963);Gain of methylation at K132 (P = 0.0963);Gain of methylation at K132 (P = 0.0963);.;.;Gain of methylation at K132 (P = 0.0963);.;.;.;Gain of methylation at K132 (P = 0.0963);
MVP		0.79
MPC		0.65
ClinPred		0.090	T
GERP RS		-11
Varity_R		0.31
gMVP		0.13

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: rs137852792; hg19: chr17-7578544; COSMIC: COSV53606125; COSMIC: COSV53606125;