rs766765429

chr17-7676550-A-Cchr17-7676550-A-Gchr17-7676550-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP3

The NM_000546.6(TP53):c.45T>G(p.Ser15Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,818 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar. Synonymous variant affecting the same amino acid position (i.e. S15S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TP53 NM_000546.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0910

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 5 ACMG points.

• PM1: In a modified_residue Phosphoserine; by CDK5, PRPK, AMPK, NUAK1 and ATM (size 0) in uniprot entity P53_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.79

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TP53	NM_000546.6	c.45T>G	p.Ser15Arg	missense_variant	2/11	ENST00000269305.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TP53	ENST00000269305.9	c.45T>G	p.Ser15Arg	missense_variant	2/11	1	NM_000546.6	P1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461818 Hom.: 0 Cov.: 35 AF XY: 0.00000138 AC XY: 1 AN XY: 727206

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 30

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
Cadd	Benign	19
Dann	Uncertain	1.0
DEOGEN2	Benign	0.067	T;T;D;.;.;.;D;.;T;T;T;.
Eigen	Benign	-0.0052
Eigen_PC	Benign	-0.16
FATHMM_MKL	Benign	0.66	D
LIST_S2	Benign	0.79	T;T;.;T;T;.;T;T;D;T;T;T
M_CAP	Pathogenic	0.73	D
MetaRNN	Pathogenic	0.79	D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	0.99	D;D;D;D;D;D
PROVEAN	Benign	-2.2	N;N;N;.;N;N;N;.;N;D;.;D
REVEL	Pathogenic	0.72
Sift	Benign	0.040	D;D;D;.;D;D;D;.;D;D;.;D
Sift4G	Uncertain	0.030	D;D;D;D;D;D;D;D;.;.;D;.
Polyphen		1.0	D;.;D;D;D;D;D;.;D;D;.;.
Vest4		0.80
MutPred		0.54		Loss of phosphorylation at S15 (P = 0.0197);Loss of phosphorylation at S15 (P = 0.0197);Loss of phosphorylation at S15 (P = 0.0197);Loss of phosphorylation at S15 (P = 0.0197);Loss of phosphorylation at S15 (P = 0.0197);Loss of phosphorylation at S15 (P = 0.0197);Loss of phosphorylation at S15 (P = 0.0197);Loss of phosphorylation at S15 (P = 0.0197);Loss of phosphorylation at S15 (P = 0.0197);Loss of phosphorylation at S15 (P = 0.0197);Loss of phosphorylation at S15 (P = 0.0197);Loss of phosphorylation at S15 (P = 0.0197);
MVP		0.96
MPC		1.7
ClinPred		0.93	D
GERP RS		-1.6
Varity_R		0.84
gMVP		0.80

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: chr17-7579868;