NM_000546.6:c.19G>A

Variant names:

• chr17-7676576-C-T
• NM_000546.6:c.19G>A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_000546.6(TP53):​c.19G>A​(p.Asp7Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: TP53 NM_000546.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.88

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.

• 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.19G>A	p.Asp7Asn	missense_variant	Exon 2 of 11	ENST00000269305.9	NP_000537.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TP53	ENST00000269305.9	c.19G>A	p.Asp7Asn	missense_variant	Exon 2 of 11	1	NM_000546.6	ENSP00000269305.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1

Jan 13, 2020

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.D7N variant (also known as c.19G>A), located in coding exon 1 of the TP53 gene, results from a G to A substitution at nucleotide position 19. The aspartic acid at codon 7 is replaced by asparagine, an amino acid with highly similar properties. Studies conducted in human cell lines indicate this alteration remains proficient at growth suppression (Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is poorly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.039	T;T;D;.;.;.;D;.;T;T;T;.
Eigen	Uncertain	0.27
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Uncertain	0.95	D;D;.;D;D;.;D;D;D;D;D;D
M_CAP	Pathogenic	0.33	D
MetaRNN	Uncertain	0.50	D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Benign	1.8	.;.;L;L;L;L;L;.;.;.;.;.
PROVEAN	Benign	-0.78	N;N;N;.;N;N;N;.;N;N;.;N
REVEL	Uncertain	0.40
Sift	Uncertain	0.0040	D;D;D;.;D;D;D;.;D;D;.;D
Sift4G	Uncertain	0.050	T;T;T;T;T;T;T;T;.;.;D;.
Polyphen		0.90	P;.;D;P;P;P;D;.;B;D;.;.
Vest4		0.21
MutPred		0.36		Gain of glycosylation at S6 (P = 0.1308);Gain of glycosylation at S6 (P = 0.1308);Gain of glycosylation at S6 (P = 0.1308);Gain of glycosylation at S6 (P = 0.1308);Gain of glycosylation at S6 (P = 0.1308);Gain of glycosylation at S6 (P = 0.1308);Gain of glycosylation at S6 (P = 0.1308);Gain of glycosylation at S6 (P = 0.1308);Gain of glycosylation at S6 (P = 0.1308);Gain of glycosylation at S6 (P = 0.1308);Gain of glycosylation at S6 (P = 0.1308);Gain of glycosylation at S6 (P = 0.1308);
MVP		0.91
MPC		1.5
ClinPred		0.84	D
GERP RS		5.4
Varity_R		0.16
gMVP		0.14

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-7579894;