rs1553863660

Positions:

• chr3-189894258-G-A
• chr3-189894258-G-C

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.1799G>A​(p.Gly600Asp) 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G600V) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TP63 NM_003722.5 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.41

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 chr3-189894258-G-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, 0.96
• PP5: Variant 3-189894258-G-A is Pathogenic according to our data. Variant chr3-189894258-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 544362.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TP63	NM_003722.5	c.1799G>A	p.Gly600Asp	missense_variant	14/14	ENST00000264731.8	NP_003713.3
TP63	NM_001114980.2	c.1517G>A	p.Gly506Asp	missense_variant	12/12	ENST00000354600.10	NP_001108452.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TP63	ENST00000264731.8	c.1799G>A	p.Gly600Asp	missense_variant	14/14	1	NM_003722.5	ENSP00000264731.3
TP63	ENST00000354600.10	c.1517G>A	p.Gly506Asp	missense_variant	12/12	1	NM_001114980.2	ENSP00000346614.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

TP63-Related Spectrum Disorders Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 16, 2020

For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has been observed in individual(s) with clinical features of ankyloblepharon-ectodermal defects-cleft lip/palate (AEC) syndrome (PMID: 22329826, 20491771, 16190990, Invitae). It has also been observed to segregate with disease in related individuals. This variant is also known as G506D and p.Gly561Asp. ClinVar contains an entry for this variant (Variation ID: 544362). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with aspartic acid at codon 600 of the TP63 protein (p.Gly600Asp). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and aspartic acid. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.38
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.64	D;.;.;.;.
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.96	D;D;D;D;D
MetaSVM	Uncertain	0.33	D
MutationAssessor	Uncertain	2.2	M;.;.;.;.
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-2.6	D;D;N;N;N
REVEL	Pathogenic	0.85
Sift	Uncertain	0.0010	D;D;D;D;D
Sift4G	Uncertain	0.0020	D;D;D;D;D
Polyphen		1.0	D;.;D;D;.
Vest4		0.94
MutPred		0.86		Loss of MoRF binding (P = 0.0668);.;.;.;.;
MVP		0.97
MPC		1.7
ClinPred		0.97	D
GERP RS		5.9
Varity_R		0.90
gMVP		0.95

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: rs1553863660; hg19: chr3-189612047;