rs121908839

chr3-189867905-C-T

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_003722.5(TP63):c.955C>T(p.Arg319Cys) variant causes a missense change. 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R319H) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TP63 NM_003722.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 3.97

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]

ACMG classification

Verdict is Pathogenic. Variant got 19 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain 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 chr3-189867906-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 265276.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant where missense usually causes diseases, TP63
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.992
• PP5: Variant 3-189867905-C-T is Pathogenic according to our data. Variant chr3-189867905-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 6532.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-189867905-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TP63	NM_003722.5	c.955C>T	p.Arg319Cys	missense_variant	7/14	ENST00000264731.8
TP63	NM_001114980.2	c.673C>T	p.Arg225Cys	missense_variant	5/12	ENST00000354600.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TP63	ENST00000264731.8	c.955C>T	p.Arg319Cys	missense_variant	7/14	1	NM_003722.5	P4
TP63	ENST00000354600.10	c.673C>T	p.Arg225Cys	missense_variant	5/12	1	NM_001114980.2	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Nov 14, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Sep 28, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 05, 2022	Identified in multiple individuals with TP63-related disorders referred for genetic testing at GeneDx and in published literature (Ianakiev et al., 2000; Yang et al., 2017); Published functional studies demonstrate interference with TP63 protein function and inhibition of the wild-type protein in a dominant-negative manner (Khokhar et al., 2008; Serra et al., 2011); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 22574117, 24460914, 12161593, 22069181, 29620206, 21211247, 15324320, 31050217, 28420484, 18626511, 10839977, 17224651, 21652629) -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 15, 2021	- -

TP63-Related Spectrum Disorders Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Apr 14, 2023

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects TP63 function (PMID: 18626511). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt TP63 protein function. ClinVar contains an entry for this variant (Variation ID: 6532). This variant is also known as 982T->C, R280C. This missense change has been observed in individual(s) with clinical features of ectrodactyly, ectodermal dysplasia, cleft lip/palate syndrome (PMID: 10839977, 12161593, 21211247, 31050217). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 319 of the TP63 protein (p.Arg319Cys). -

Split hand-foot malformation 4 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 01, 2000

- -

Ectrodactyly, ectodermal dysplasia, and cleft lip-palate syndrome 3 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Lifecell International Pvt. Ltd

-

A Heterozygous Missense variant c.955C>T in Exon 7 of the TP63 gene that results in the amino acid substitution p.Arg319Cys was identified. The observed variant is novel in gnomAD exomes and genomes, respectively. The severity of the impact of this variant on the protein is medium, based on the effect of the protein and REVEL score . Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. . ClinVar has also classified this variant as Pathogenic (Variant ID: 6532). The observed variant previously been reported in the patient affected with ectrodactyly (Ianakiev P et. al 2000). Based on the above evidence this variant has been classified as Pathogenic according to the ACMG guidelines. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
Cadd	Pathogenic	30
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.99	D;.;.;.;.;.;.;.;.;.;.
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.50	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.93	D
MutationAssessor	Uncertain	2.8	M;M;M;M;M;.;.;.;.;.;.
MutationTaster	Benign	1.0	A;A;A;A;A;A;A;A;A;A;A;A
PrimateAI	Pathogenic	0.95	D
PROVEAN	Pathogenic	-7.4	D;D;D;D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D;D;D;D;D;D;D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;D;D;D;D
Polyphen		1.0	D;D;D;D;D;D;D;D;.;D;.
Vest4		0.94
MutPred		0.99		Loss of sheet (P = 0.1907);Loss of sheet (P = 0.1907);Loss of sheet (P = 0.1907);Loss of sheet (P = 0.1907);Loss of sheet (P = 0.1907);.;.;.;.;.;.;
MVP		0.98
MPC		1.8
ClinPred		1.0	D
GERP RS		4.7
Varity_R		0.95
gMVP		0.96

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

Other links and lift over

dbSNP: rs121908839; hg19: chr3-189585694;