rs121908841

chr3-189868615-G-Achr3-189868615-G-Cchr3-189868615-G-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.1028G>A(p.Arg343Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,816 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R343W) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TP63 NM_003722.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 9.89

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 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 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 chr3-189868614-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 279913.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 3-189868615-G-A is Pathogenic according to our data. Variant chr3-189868615-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 6534.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-189868615-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TP63	NM_003722.5	c.1028G>A	p.Arg343Gln	missense_variant	8/14	ENST00000264731.8
TP63	NM_001114980.2	c.746G>A	p.Arg249Gln	missense_variant	6/12	ENST00000354600.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TP63	ENST00000264731.8	c.1028G>A	p.Arg343Gln	missense_variant	8/14	1	NM_003722.5	P4
TP63	ENST00000354600.10	c.746G>A	p.Arg249Gln	missense_variant	6/12	1	NM_001114980.2	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461816 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727210

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

TP63-Related Spectrum Disorders Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Nov 17, 2023	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 343 of the TP63 protein (p.Arg343Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Rapp-Hodgkin syndrome and acro-dermo-ungual-lacrimal-tooth (ADULT) syndrome and ectrodactyly, ectodermal dysplasia, and cleft lip/palate (EEC) syndrome (PMID: 10839977, 12525544, 26882220, 27028492). This variant is also known as p.Arg304Gln. ClinVar contains an entry for this variant (Variation ID: 6534). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on TP63 protein function. This variant disrupts the p.Arg343 amino acid residue in TP63. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10535733, 12525544, 19353588, 20180707, 21652629, 23355676, 24734328). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	research	Division of Human Genetics, National Health Laboratory Service/University of the Witwatersrand	Jul 01, 2023	- -

Ectrodactyly, ectodermal dysplasia, and cleft lip-palate syndrome 3 Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 01, 2000	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Jul 18, 2022	- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 02, 2018

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Dec 08, 2021

Reported previously in the heterozygous state, using alternate nomenclature (R304Q), in association with ectrodactyly-ectodermal dysplasia-clefting (EEC) syndrome (Ianakiev et al., 2000; van Bokhoven et al., 2001; Barrow et al., 2002; Dianzani et al., 2003; de Mollerat et al., 2003); Observed in a female who lacked ectrodactyly, thus diagnosed with Rapp-Hodgkin syndrome, and her daughter who reportedly had all of the cardinal features of EEC syndrome (Brueggemann et al., 2016); Published functional studies demonstrate that this variant abolishes p63 transcriptional activity at promoters of the KRT14, IRF6, and DSC3 genes, and impairs its intrinsic DNA binding ability (Russo et al., 2018); Not observed in large population cohorts (Lek et al., 2016); Also known as p.R304Q; This variant is associated with the following publications: (PMID: 10839977, 12161593, 14684701, 12525544, 27028492, 29130604, 32224865, 31682841, 17224651, 21652629, 29339502, 11462173, 26882220) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
Cadd	Pathogenic	33
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.99	D;.;.;.;.;.;.;.;.;.;.
Eigen	Pathogenic	0.98
Eigen_PC	Pathogenic	0.95
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.72	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Uncertain	2.9	M;M;M;M;M;.;.;.;.;.;.
MutationTaster	Benign	1.0	A;A;A;A;A;A;A;A;A;A;A;A
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-3.7	D;D;D;D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.95
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		0.97
MutPred		0.98		Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);.;.;.;.;.;.;
MVP		0.99
MPC		0.83
ClinPred		0.99	D
GERP RS		5.8
Varity_R		0.96
gMVP		0.94

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: rs121908841; hg19: chr3-189586404; COSMIC: COSV53215406; COSMIC: COSV53215406;