rs912136376

Positions:

• chr17-7673322-T-A
• chr17-7673322-T-C

Variant summary

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

The ENST00000420246.6(TP53):​c.1011A>T​(p.Gln337His) 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. 9/15 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. Q337Q) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: TP53 ENST00000420246.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.430

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 HIPK1 (size 270) in uniprot entity P53_HUMAN there are 496 pathogenic changes around while only 97 benign (84%) in ENST00000420246.6
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13747862).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TP53	NM_000546.6	c.993+213A>T		intron_variant		ENST00000269305.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TP53	ENST00000269305.9	c.993+213A>T		intron_variant		1	NM_000546.6	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.059	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	9.3
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0065	.;T;.;.;.
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.56
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.38	T;T;T;.;T
M_CAP	Uncertain	0.092	D
MetaRNN	Benign	0.14	T;T;T;T;T
MetaSVM	Pathogenic	1.0	D
MutationTaster	Benign	0.99	D;D;D;D;D;N
PROVEAN	Benign	-0.27	.;.;.;N;.
REVEL	Uncertain	0.31
Sift	Benign	0.032	.;.;.;D;.
Sift4G	Uncertain	0.035	D;D;D;D;D
Polyphen		0.98	.;.;D;D;.
Vest4		0.23
MutPred		0.050		.;.;Gain of catalytic residue at E339 (P = 0.0766);Gain of catalytic residue at E339 (P = 0.0766);.;
MVP		0.85
ClinPred		0.22	T
GERP RS		-0.0056

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: chr17-7576640;