rs1057517841

chr3-189890863-T-C

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1 PM2 PP2 PP3_Strong PP5_Very_Strong

The NM_003722.5(TP63):c.1727T>C(p.Ile576Thr) 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 Pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TP63 NM_003722.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 7.67

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 17 ACMG points.

• PM1: In a domain SAM (size 66) in uniprot entity P63_HUMAN there are 29 pathogenic changes around while only 2 benign (94%) in NM_003722.5
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, TP63
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.958
• PP5: Variant 3-189890863-T-C is Pathogenic according to our data. Variant chr3-189890863-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 372540.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TP63	NM_003722.5	c.1727T>C	p.Ile576Thr	missense_variant	13/14	ENST00000264731.8
TP63	NM_001114980.2	c.1445T>C	p.Ile482Thr	missense_variant	11/12	ENST00000354600.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TP63	ENST00000264731.8	c.1727T>C	p.Ile576Thr	missense_variant	13/14	1	NM_003722.5	P4
TP63	ENST00000354600.10	c.1445T>C	p.Ile482Thr	missense_variant	11/12	1	NM_001114980.2	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

TP63-Related Spectrum Disorders Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

May 04, 2021

This variant is not present in population databases (ExAC no frequency). This sequence change replaces isoleucine with threonine at codon 576 of the TP63 protein (p.Ile576Thr). The isoleucine residue is highly conserved and there is a moderate physicochemical difference between isoleucine and threonine. This variant has been observed in individual(s) with ankyloblepharon-ectodermal dysplasia-clefting (AEC) syndrome (PMID: 11159940, 20156774, 30809829, Invitae). It has also been observed to segregate with disease in related individuals. This variant is also known as Ile541Thr, Ile537Thr, or Ile482Thr. ClinVar contains an entry for this variant (Variation ID: 372540). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this variant affects TP63 protein function (PMID: 21652629, 21615690). -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Aug 25, 2015

The I576T missense variant in the TP63 gene has been reported previously in association with Hay-Wells syndrome using alternate nomenclature (McGrath et al., 2001; Tomkova et al., 2010; Alessandro et al., 2013). This variant is present in the hydrophobic core of the SAM domain, and studies have shown that replacing the non-polar Isoleucine residue with a polar Threonine residue destabilizes the protein and affects its function (Sathyamurthy et al., 2011; Browne et al., 2011). Therefore, we interpret this variant as pathogenic. -

TP63-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 25, 2023

The TP63 c.1727T>C variant is predicted to result in the amino acid substitution p.Ile576Thr. This variant was reported in multiple individuals with Hay-Wells syndrome McGrath et al. 2001. PubMed ID: 11159940, reported as I541T; Tomková et al. 2010. PubMed ID: 20156774, reported as I537T; Serra et al. 2021. PubMed ID: 34583755). In vitro functional analysis indicates that this amino acid change impairs activity (Browne et al. 2011. PubMed ID: 21652629, reported as I537T). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.39
Cadd	Pathogenic	26
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.46	T;.;.;.;.
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D
M_CAP	Uncertain	0.18	D
MetaRNN	Pathogenic	0.96	D;D;D;D;D
MetaSVM	Uncertain	0.38	D
MutationAssessor	Benign	1.6	L;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-1.6	N;N;N;N;N
REVEL	Pathogenic	0.79
Sift	Uncertain	0.0010	D;D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D;D
Polyphen		0.98	D;.;P;P;.
Vest4		0.99
MutPred		0.86		Gain of disorder (P = 0.0399);.;.;.;.;
MVP		0.98
MPC		1.7
ClinPred		0.94	D
GERP RS		6.0
Varity_R		0.59
gMVP		0.80

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: rs1057517841; hg19: chr3-189608652;