3-189866712-G-C

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Moderate

The NM_003722.5(TP63):c.797G>C(p.Arg266Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R266Q) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

TP63
NM_003722.5 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 9.90

Publications

0 publications found

Variant links:

Genes affected

TP63 (HGNC:15979): (tumor protein p63) This gene encodes a member of the p53 family of transcription factors. The functional domains of p53 family proteins include an N-terminal transactivation domain, a central DNA-binding domain and an oligomerization domain. Alternative splicing of this gene and the use of alternative promoters results in multiple transcript variants encoding different isoforms that vary in their functional properties. These isoforms function during skin development and maintenance, adult stem/progenitor cell regulation, heart development and premature aging. Some isoforms have been found to protect the germline by eliminating oocytes or testicular germ cells that have suffered DNA damage. Mutations in this gene are associated with ectodermal dysplasia, and cleft lip/palate syndrome 3 (EEC3); split-hand/foot malformation 4 (SHFM4); ankyloblepharon-ectodermal defects-cleft lip/palate; ADULT syndrome (acro-dermato-ungual-lacrimal-tooth); limb-mammary syndrome; Rap-Hodgkin syndrome (RHS); and orofacial cleft 8. [provided by RefSeq, Aug 2016]

TP63 Gene-Disease associations (from GenCC):

ADULT syndrome
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, Orphanet
ankyloblepharon-ectodermal defects-cleft lip/palate syndrome
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, Orphanet
ectrodactyly, ectodermal dysplasia, and cleft lip-palate syndrome 3
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
limb-mammary syndrome
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, Orphanet
Rapp-Hodgkin syndrome
Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
premature ovarian failure 21
Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
split hand-foot malformation 4
Inheritance: AD Classification: MODERATE Submitted by: Illumina
EEC syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
split hand-foot malformation
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

TP63 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 13 ACMG points.

PM1

In a strand (size 6) in uniprot entity P63_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_003722.5

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr3-189866712-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 6550.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP2

Missense variant in the TP63 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 73 curated pathogenic missense variants (we use a threshold of 10). The gene has 15 curated benign missense variants. Gene score misZ: 2.2077 (below the threshold of 3.09). Trascript score misZ: 3.5096 (above the threshold of 3.09). GenCC associations: The gene is linked to Rapp-Hodgkin syndrome, ADULT syndrome, premature ovarian failure 21, limb-mammary syndrome, ectrodactyly, ectodermal dysplasia, and cleft lip-palate syndrome 3, ankyloblepharon-ectodermal defects-cleft lip/palate syndrome, EEC syndrome, split hand-foot malformation, split hand-foot malformation 4.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.993

PP5

Variant 3-189866712-G-C is Pathogenic according to our data. Variant chr3-189866712-G-C is described in CliVar as Likely_pathogenic. Clinvar id is 30348.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-189866712-G-C is described in CliVar as Likely_pathogenic. Clinvar id is 30348.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-189866712-G-C is described in CliVar as Likely_pathogenic. Clinvar id is 30348.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-189866712-G-C is described in CliVar as Likely_pathogenic. Clinvar id is 30348.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-189866712-G-C is described in CliVar as Likely_pathogenic. Clinvar id is 30348.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-189866712-G-C is described in CliVar as Likely_pathogenic. Clinvar id is 30348.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-189866712-G-C is described in CliVar as Likely_pathogenic. Clinvar id is 30348.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-189866712-G-C is described in CliVar as Likely_pathogenic. Clinvar id is 30348.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-189866712-G-C is described in CliVar as Likely_pathogenic. Clinvar id is 30348.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-189866712-G-C is described in CliVar as Likely_pathogenic. Clinvar id is 30348.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-189866712-G-C is described in CliVar as Likely_pathogenic. Clinvar id is 30348.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-189866712-G-C is described in CliVar as Likely_pathogenic. Clinvar id is 30348.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-189866712-G-C is described in CliVar as Likely_pathogenic. Clinvar id is 30348.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-189866712-G-C is described in CliVar as Likely_pathogenic. Clinvar id is 30348.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-189866712-G-C is described in CliVar as Likely_pathogenic. Clinvar id is 30348.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-189866712-G-C is described in CliVar as Likely_pathogenic. Clinvar id is 30348.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-189866712-G-C is described in CliVar as Likely_pathogenic. Clinvar id is 30348.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-189866712-G-C is described in CliVar as Likely_pathogenic. Clinvar id is 30348.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-189866712-G-C is described in CliVar as Likely_pathogenic. Clinvar id is 30348.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-189866712-G-C is described in CliVar as Likely_pathogenic. Clinvar id is 30348.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-189866712-G-C is described in CliVar as Likely_pathogenic. Clinvar id is 30348.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-189866712-G-C is described in CliVar as Likely_pathogenic. Clinvar id is 30348.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-189866712-G-C is described in CliVar as Likely_pathogenic. Clinvar id is 30348.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-189866712-G-C is described in CliVar as Likely_pathogenic. Clinvar id is 30348.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TP63	NM_003722.5 link	c.797G>C	p.Arg266Pro	missense_variant	Exon 6 of 14	ENST00000264731.8	NP_003713.3	Q9H3D4-1A0A0S2Z4N5
TP63	NM_001114980.2 link	c.515G>C	p.Arg172Pro	missense_variant	Exon 4 of 12	ENST00000354600.10	NP_001108452.1	Q9H3D4-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TP63	ENST00000264731.8 link	c.797G>C	p.Arg266Pro	missense_variant	Exon 6 of 14	1	NM_003722.5	ENSP00000264731.3		Q9H3D4-1
TP63	ENST00000354600.10 link	c.515G>C	p.Arg172Pro	missense_variant	Exon 4 of 12	1	NM_001114980.2	ENSP00000346614.5		Q9H3D4-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Pathogenic:1

Dec 21, 2023

GeneDx

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Identified in a patient and her father both with TP63-related ectodermal dysplasia and oral clefting spectrum in published literature (PMID: 21204238); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Also known as p.R237P; This variant is associated with the following publications: (PMID: 17224651, 21652629, 21204238, 32021595) -

Ectrodactyly, ectodermal dysplasia, and cleft lip-palate syndrome 3

Pathogenic:1

Jan 01, 2011

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.56

BayesDel_noAF

Pathogenic

0.56

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.99

D;.;.;.;.;.;.;.;.;.;.

Eigen

Pathogenic

0.97

Eigen_PC

Pathogenic

0.93

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

D;D;D;D;D;D;D;D;D;D;D

M_CAP

Pathogenic

0.82

MetaRNN

Pathogenic

0.99

D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Pathogenic

0.95

MutationAssessor

Uncertain

2.7

M;M;M;M;M;.;.;.;.;.;.

PhyloP100

9.9

PrimateAI

Pathogenic

0.87

PROVEAN

Pathogenic

-6.4

D;D;D;D;D;D;D;D;D;D;D

REVEL

Pathogenic

0.96

Sift

Uncertain

0.0020

D;D;D;D;D;D;D;D;D;D;D

Sift4G

Pathogenic

0.0010

D;D;D;D;D;D;D;D;D;D;D

Polyphen

1.0

D;D;D;D;D;D;D;D;.;D;.

Vest4

0.98

MutPred

0.96

Gain of disorder (P = 0.0826);Gain of disorder (P = 0.0826);Gain of disorder (P = 0.0826);Gain of disorder (P = 0.0826);Gain of disorder (P = 0.0826);.;.;.;.;.;.;

MVP

0.99

MPC

1.8

ClinPred

0.99

GERP RS

5.6

Varity_R

0.99

gMVP

0.99

Mutation Taster

=0/100

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over