rs797044484

chr3-189868624-C-Gchr3-189868624-C-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PP2 PP3_Strong PP5_Moderate

The NM_003722.5(TP63):c.1037C>G(p.Ala346Gly) 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, single submitter P:1
• Conservation: PhyloP100: 7.82

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 11 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, 5 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, 0.98
• PP5: Variant 3-189868624-C-G is Pathogenic according to our data. Variant chr3-189868624-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 208418.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TP63	NM_003722.5	c.1037C>G	p.Ala346Gly	missense_variant	8/14	ENST00000264731.8
TP63	NM_001114980.2	c.755C>G	p.Ala252Gly	missense_variant	6/12	ENST00000354600.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TP63	ENST00000264731.8	c.1037C>G	p.Ala346Gly	missense_variant	8/14	1	NM_003722.5	P4
TP63	ENST00000354600.10	c.755C>G	p.Ala252Gly	missense_variant	6/12	1	NM_001114980.2	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Pathogenic, criteria provided, single submitter

research

Laboratory of Human Genetics, Universidade de São Paulo

Feb 11, 2014

The proband presents with EEC syndrome. Since the proband’s son does not have cleft lip/palate, his phenotype is similar to that of ADULT syndrome, which may not include clefting, breast hipoplasia or freckling. This clinical overlap could demonstrate that the distinctions between EEC and ADULT syndromes are somewhat artificial. The father of the proband allegedly presented only SHFM, without other manifestations. This could indicate that the mutation c.1037C>G might also be associated with nonsyndromic SHFM. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.49
Cadd	Pathogenic	27
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	D;.;.;.;.;.;.;.;.;.;.
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.81
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	0.64	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.95	D
MutationAssessor	Uncertain	2.8	M;M;M;M;M;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-3.7	D;D;D;D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.86
Sift	Pathogenic	0.0	D;D;D;D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.0040	D;D;D;D;D;D;D;D;D;D;D
Polyphen		0.85	P;P;P;P;P;P;P;P;.;P;.
Vest4		0.96
MutPred		0.88		Gain of disorder (P = 0.0943);Gain of disorder (P = 0.0943);Gain of disorder (P = 0.0943);Gain of disorder (P = 0.0943);Gain of disorder (P = 0.0943);.;.;.;.;.;.;
MVP		0.97
MPC		1.3
ClinPred		0.99	D
GERP RS		5.8
Varity_R		0.95
gMVP		0.90

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: rs797044484; hg19: chr3-189586413;