rs144366923

Variant names:

• chr17-7666228-C-G
• rs144366923
• ENST00000359597.8:c.1010G>C
• TP53 p.Arg337Thr

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The ENST00000359597.8(TP53):​c.1010G>C​(p.Arg337Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00183 in 649,822 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/15 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as not provided (no stars). The gene TP53 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.0060 (10 hom., cov: 31)
  • Exomes 𝑓: 0.00056 (1 hom.)
• Consequence: TP53 ENST00000359597.8 missense
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 0.721
• Publications: 3 publications found

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]

TP53 Gene-Disease associations (from GenCC):

• breast cancer

  Inheritance: AD Classification: DEFINITIVE Submitted by: Ambry Genetics
• Li-Fraumeni syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, ClinGen, G2P
• Li-Fraumeni syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Genomics England PanelApp
• adrenocortical carcinoma, hereditary

  Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics
• sarcoma

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• bone marrow failure syndrome 5

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• colorectal cancer

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• choroid plexus carcinoma

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Specifications for TP53 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005035609).
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.006 (912/152028) while in subpopulation AFR AF = 0.0211 (875/41478). AF 95% confidence interval is 0.0199. There are 10 homozygotes in GnomAd4. There are 429 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 912 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000359597.8. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
There are no transcript annotations for this variant.

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TP53	ENST00000359597.8	TSL:1	c.1010G>C	p.Arg337Thr	missense	Exon 9 of 9	ENSP00000352610.4	J3KP33
	TP53	ENST00000413465.6	TSL:1	c.783-4214G>C		intron	N/A	ENSP00000410739.2	E7EQX7
	TP53	ENST00000714356.1		c.1000G>C	p.Gly334Arg	missense	Exon 10 of 10	ENSP00000519623.1	A0AAQ5BHY1

Frequencies

GnomAD3 genomes AF: 0.00600 AC: 912 AN: 151910 Hom.: 10 Cov.: 31

Gnomad AFR AF: 0.0212

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00184

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00192

GnomAD2 exomes AF: 0.000545 AC: 54 AN: 99062 AF XY: 0.000471

Gnomad AFR exome AF: 0.0111

Gnomad AMR exome AF: 0.000414

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000250

Gnomad OTH exome AF: 0.000667

GnomAD4 exome AF: 0.000556 AC: 277 AN: 497794 Hom.: 1 Cov.: 0 AF XY: 0.000462 AC XY: 125 AN XY: 270802

African (AFR) AF: 0.0180 AC: 236 AN: 13128

American (AMR) AF: 0.000329 AC: 9 AN: 27324

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18624

East Asian (EAS) AF: 0.00 AC: 0 AN: 28686

South Asian (SAS) AF: 0.0000372 AC: 2 AN: 53790

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32414

Middle Eastern (MID) AF: 0.000254 AC: 1 AN: 3936

European-Non Finnish (NFE) AF: 0.0000137 AC: 4 AN: 291574

Other (OTH) AF: 0.000883 AC: 25 AN: 28318

GnomAD4 genome AF: 0.00600 AC: 912 AN: 152028 Hom.: 10 Cov.: 31 AF XY: 0.00577 AC XY: 429 AN XY: 74314

African (AFR) AF: 0.0211 AC: 875 AN: 41478

American (AMR) AF: 0.00184 AC: 28 AN: 15240

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5154

South Asian (SAS) AF: 0.00 AC: 0 AN: 4804

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10594

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000736 AC: 5 AN: 67976

Other (OTH) AF: 0.00190 AC: 4 AN: 2106

Alfa AF: 0.00367 Hom.: 1

Bravo AF: 0.00687

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: not provided

Revision: no classification provided

Pathogenic	VUS	Benign	Condition
-	-	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	2.3
DANN	Benign	0.55
DEOGEN2	Benign	0.017	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.013	N
LIST_S2	Benign	0.29	T
MetaRNN	Benign	0.0050	T
MetaSVM	Uncertain	0.54	D
PhyloP100		0.72
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.22
Sift	Uncertain	0.019	D
Sift4G	Uncertain	0.015	D
Mutation Taster		=97/3	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs144366923;

hg19: chr17-7569546;

COSMIC: COSV53035811;