rs121908847

Positions:

• chr3-189868641-A-G
• chr3-189868641-A-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP2 PP3_Strong

The NM_003722.5(TP63):​c.1054A>G​(p.Arg352Gly) variant causes a missense change involving the alteration of a non-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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TP63 NM_003722.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: 1.44

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 Likely_pathogenic. Variant got 9 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, 2 uncertain 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, 0.99

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TP63	NM_003722.5	c.1054A>G	p.Arg352Gly	missense_variant	8/14	ENST00000264731.8
TP63	NM_001114980.2	c.772A>G	p.Arg258Gly	missense_variant	6/12	ENST00000354600.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TP63	ENST00000264731.8	c.1054A>G	p.Arg352Gly	missense_variant	8/14	1	NM_003722.5	P4
TP63	ENST00000354600.10	c.772A>G	p.Arg258Gly	missense_variant	6/12	1	NM_001114980.2	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Orofacial cleft 8 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 01, 2006

- -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Servicio Canario de Salud, Hospital Universitario Nuestra Sra. de Candelaria

May 08, 2022

The c.1054A>G (p.Arg352Gly) TP63 variant has been reported in our laboratory in a 41-year-old woman with diagnosis of ectrodactyly and asymptomatic parents. Patient with two previous legal abortions due to fetuses affected by ectrodactyly, in one of them the presence of this heterozygous variant could be confirmed. It has been previously reported in non-syndromic cleft lip (PMID 16740912). This variant is not present in population databases (gnomAD no frequency). ClinVar contains an entry for this variant (Variation ID: 6547). In silico analysis (CADD, Mutation Taster, SIFT, PolyPhen2) supports that this missense variant has a deleterious effect on protein structure/function. To date there are no functional/experimental studies that evaluate the impact on protein. In summary, c.1054A>G (p.Arg352Gly) TP63 variant meets our criteria to be classified as Variant of Uncertain Significance-Probably Pathogenic based upon its absence from controls, computational evidence of pathogenicity and and the clinical correlation in this family´s phenotype. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.50
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	D;.;.;.;.;.;.;.;.;.;.
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.66	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.99	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	0.85	D
PROVEAN	Pathogenic	-6.4	D;D;D;D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	D;D;D;D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.0050	D;D;D;D;D;D;D;D;D;D;D
Polyphen		1.0	D;D;D;D;D;D;D;D;.;D;.
Vest4		0.96
MutPred		0.93		Loss of stability (P = 0.0966);Loss of stability (P = 0.0966);Loss of stability (P = 0.0966);Loss of stability (P = 0.0966);Loss of stability (P = 0.0966);.;.;.;.;.;.;
MVP		0.99
MPC		0.96
ClinPred		0.96	D
GERP RS		2.1
Varity_R		0.98
gMVP		0.99

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: rs121908847; hg19: chr3-189586430;