17-7673773-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PM5

The NM_000546.6(TP53):​c.847C>A​(p.Arg283Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,880 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R283C) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 31)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

TP53
NM_000546.6 missense

Scores

6
8
5

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.69
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 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;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr17-7673773-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TP53NM_000546.6 linkc.847C>A p.Arg283Ser missense_variant Exon 8 of 11 ENST00000269305.9 NP_000537.3 P04637-1K7PPA8Q53GA5

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TP53ENST00000269305.9 linkc.847C>A p.Arg283Ser missense_variant Exon 8 of 11 1 NM_000546.6 ENSP00000269305.4 P04637-1

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD3 exomes
AF:
0.00000398
AC:
1
AN:
251440
Hom.:
0
AF XY:
0.00000736
AC XY:
1
AN XY:
135894
show subpopulations
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:
0.0000462
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461880
Hom.:
0
Cov.:
33
AF XY:
0.00000138
AC XY:
1
AN XY:
727244
show subpopulations
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:
0.00
Gnomad4 FIN exome
AF:
0.0000187
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
31
ExAC
AF:
0.00000824
AC:
1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.98
BayesDel_addAF
Pathogenic
0.28
D
BayesDel_noAF
Pathogenic
0.17
CADD
Uncertain
25
DANN
Uncertain
0.98
DEOGEN2
Uncertain
0.67
D;.;.;.;.;T;T;.;D;.;.;.;.;.;.;D;.;.;.
Eigen
Benign
-0.10
Eigen_PC
Benign
-0.069
FATHMM_MKL
Uncertain
0.78
D
LIST_S2
Uncertain
0.94
D;D;D;D;D;D;D;.;.;.;D;D;.;D;D;D;D;D;D
M_CAP
Pathogenic
0.55
D
MetaRNN
Uncertain
0.68
D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Benign
1.2
.;.;.;.;.;.;.;.;L;.;L;L;L;.;.;L;.;.;.
PrimateAI
Benign
0.43
T
PROVEAN
Uncertain
-2.5
D;.;.;.;.;.;.;.;D;.;.;D;D;.;.;D;.;.;N
REVEL
Pathogenic
0.69
Sift
Uncertain
0.0010
D;.;.;.;.;.;.;.;D;.;.;D;D;.;.;D;.;.;D
Sift4G
Uncertain
0.0050
D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
Polyphen
0.16, 0.028, 0.66
.;.;.;.;.;.;.;.;B;.;B;P;B;.;.;B;.;.;.
Vest4
0.53
MutPred
0.65
Gain of phosphorylation at R283 (P = 0.0042);.;.;.;.;.;.;.;Gain of phosphorylation at R283 (P = 0.0042);.;Gain of phosphorylation at R283 (P = 0.0042);Gain of phosphorylation at R283 (P = 0.0042);Gain of phosphorylation at R283 (P = 0.0042);.;.;Gain of phosphorylation at R283 (P = 0.0042);.;.;.;
MVP
0.95
MPC
0.18
ClinPred
0.75
D
GERP RS
4.0
RBP_binding_hub_radar
0.92
RBP_regulation_power_radar
2.0
Varity_R
0.95
gMVP
0.42

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs149633775; hg19: chr17-7577091; COSMIC: COSV52751436; COSMIC: COSV52751436; API