rs121908843

Positions:

• chr3-189890817-T-G

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Moderate

The NM_003722.5(TP63):​c.1681T>G​(p.Cys561Gly) 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. C561R) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TP63 NM_003722.5 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• 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 13 ACMG points.

• PM1: In a domain SAM (size 66) in uniprot entity P63_HUMAN there are 9 pathogenic changes around while only 1 benign (90%) 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 chr3-189890817-T-C is described in Lovd as [Likely_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, 0.98
• PP5: Variant 3-189890817-T-G is Pathogenic according to our data. Variant chr3-189890817-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 6536.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-189890817-T-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TP63	NM_003722.5	c.1681T>G	p.Cys561Gly	missense_variant	13/14	ENST00000264731.8	NP_003713.3
TP63	NM_001114980.2	c.1399T>G	p.Cys467Gly	missense_variant	11/12	ENST00000354600.10	NP_001108452.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TP63	ENST00000264731.8	c.1681T>G	p.Cys561Gly	missense_variant	13/14	1	NM_003722.5	ENSP00000264731.3
TP63	ENST00000354600.10	c.1399T>G	p.Cys467Gly	missense_variant	11/12	1	NM_001114980.2	ENSP00000346614.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Ankyloblepharon-ectodermal defects-cleft lip/palate syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Feb 01, 2001

- -

TP63-Related Spectrum Disorders Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 25, 2019

This variant is not present in population databases (ExAC no frequency). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Cys561 amino acid residue in TP63. Other variant(s) that disrupt this residue have been observed in individuals with TP63-related conditions (PMID:11159940, 19793345), which suggests that this may be a clinically significant amino acid residue. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. This variant has been reported to affect TP63 protein function (PMID:21615690). This variant has been observed in an individual affected with ankyloblepharon-ectodermal dysplasia-clefting syndrome (PMID: 11159940). This variant is also known as c.1546T>G, p.Cys526Gly in the literature. ClinVar contains an entry for this variant (Variation ID: 6536). This sequence change replaces cysteine with glycine at codon 561 of the TP63 protein (p.Cys561Gly). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and glycine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.82	D;.;.;.;.
Eigen	Pathogenic	0.69
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D;D;D;D;D
M_CAP	Uncertain	0.20	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D
MetaSVM	Uncertain	0.38	D
MutationAssessor	Uncertain	2.1	M;.;.;.;.
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-3.8	D;D;D;D;D
REVEL	Pathogenic	0.88
Sift	Benign	0.061	T;T;T;D;T
Sift4G	Uncertain	0.0030	D;D;D;D;D
Polyphen		1.0	D;.;D;D;.
Vest4		0.97
MutPred		0.92		Loss of helix (P = 0.0104);.;.;.;.;
MVP		0.98
MPC		1.7
ClinPred		0.98	D
GERP RS		5.7
Varity_R		0.83
gMVP		0.86

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs121908843; hg19: chr3-189608606;