rs121908836

Positions:

chr3-189864380-G-A

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong

The NM_003722.5(TP63):c.728G>A(p.Arg243Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,613,792 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R243W) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

TP63
NM_003722.5 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 10.0

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 19 ACMG points.

PM1

In a DNA_binding_region (size 192) in uniprot entity P63_HUMAN there are 35 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 chr3-189864379-C-T is described in Lovd as [Pathogenic].

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), TP63. . Gene score misZ 2.2077 (greater than the threshold 3.09). Trascript score misZ 3.5096 (greater than threshold 3.09). GenCC has associacion of gene with Rapp-Hodgkin syndrome, ADULT syndrome, split hand-foot malformation 4, limb-mammary syndrome, premature ovarian failure 21, split hand-foot malformation, ankyloblepharon-ectodermal defects-cleft lip/palate syndrome, EEC syndrome, ectrodactyly, ectodermal dysplasia, and cleft lip-palate syndrome 3.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.992

PP5

Variant 3-189864380-G-A is Pathogenic according to our data. Variant chr3-189864380-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 6528.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-189864380-G-A is described in Lovd as [Pathogenic]. Variant chr3-189864380-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TP63	NM_003722.5 linkuse as main transcript	c.728G>A	p.Arg243Gln	missense_variant	5/14	ENST00000264731.8	NP_003713.3
TP63	NM_001114980.2 linkuse as main transcript	c.446G>A	p.Arg149Gln	missense_variant	3/12	ENST00000354600.10	NP_001108452.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TP63	ENST00000264731.8 linkuse as main transcript	c.728G>A	p.Arg243Gln	missense_variant	5/14	1	NM_003722.5	ENSP00000264731	P4	Q9H3D4-1
TP63	ENST00000354600.10 linkuse as main transcript	c.446G>A	p.Arg149Gln	missense_variant	3/12	1	NM_001114980.2	ENSP00000346614	A1	Q9H3D4-2

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

152076

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461716

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727126

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:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000132

AC:

AN:

152076

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74278

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

TP63-Related Spectrum Disorders

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 10, 2023

This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg243 amino acid residue in TP63. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10535733, 12525544, 18626511, 18792980, 20543567, 21078104, 21652629, 23355676, 23463580). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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: 6528). This variant is also known as p.Arg204Gln. This missense change has been observed in individual(s) with autosomal dominant split-hand-split-foot malformation or SHFM and ectrodactyly-ectodermal dysplasia-cleft (EEC) syndrome (PMID: 10535733, 28293528, 29620206). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 243 of the TP63 protein (p.Arg243Gln). -

Split hand-foot malformation 4

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

3billion

May 22, 2022

The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.93; 3Cnet: 0.97). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000006528). A different missense change at the same codon (p.Arg243Trp) has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000006527). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Dec 27, 2021

Not observed at significant frequency in large population cohorts (Lek et al., 2016); 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: 31050217, 10535733, 28293528, 12939657, 29620206, 26075610, 17224651, 21652629, 33471964, 34401172, 34906519) -

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

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 15, 1999

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.55

BayesDel_noAF

Pathogenic

0.55

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.99

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

Eigen

Pathogenic

0.97

Eigen_PC

Pathogenic

0.92

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

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

M_CAP

Pathogenic

0.72

MetaRNN

Pathogenic

0.99

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

MetaSVM

Pathogenic

0.95

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

0.86

PROVEAN

Uncertain

-4.0

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

REVEL

Pathogenic

0.93

Sift

Uncertain

0.025

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

Sift4G

Uncertain

0.024

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

Polyphen

1.0

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

Vest4

0.97

MutPred

0.98

Loss of MoRF binding (P = 0.0511);Loss of MoRF binding (P = 0.0511);Loss of MoRF binding (P = 0.0511);Loss of MoRF binding (P = 0.0511);Loss of MoRF binding (P = 0.0511);.;.;.;.;.;.;

MVP

0.98

MPC

1.6

ClinPred

1.0

GERP RS

5.8

Varity_R

0.92

gMVP

0.91

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over