rs121908848

chr3-189738739-C-Achr3-189738739-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PM5 PP2 PP3

The NM_003722.5(TP63):c.289C>A(p.Arg97Ser) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R97P) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TP63 NM_003722.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.44

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 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr3-189738740-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 1677243.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP2: Missense variant where missense usually causes diseases, TP63
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.77

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TP63	NM_003722.5	c.289C>A	p.Arg97Ser	missense_variant	3/14	ENST00000264731.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TP63	ENST00000264731.8	c.289C>A	p.Arg97Ser	missense_variant	3/14	1	NM_003722.5	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.52
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
Cadd	Uncertain	25
Dann	Uncertain	0.99
DEOGEN2	Benign	0.39	T;.;.;.;.
Eigen	Benign	-0.0020
Eigen_PC	Benign	0.20
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.93	D;D;D;D;D
M_CAP	Uncertain	0.20	D
MetaRNN	Pathogenic	0.77	D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.1	L;L;L;L;L
MutationTaster	Benign	0.93	D;D;D;D;D;N
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-0.76	N;N;N;N;N
REVEL	Uncertain	0.60
Sift	Uncertain	0.0080	D;D;D;D;D
Sift4G	Benign	0.73	T;T;T;T;T
Polyphen		0.55	P;B;B;P;.
Vest4		0.86
MutPred		0.49		Gain of disorder (P = 0.028);Gain of disorder (P = 0.028);Gain of disorder (P = 0.028);Gain of disorder (P = 0.028);Gain of disorder (P = 0.028);
MVP		0.97
MPC		0.66
ClinPred		0.75	D
GERP RS		5.6
Varity_R		0.23
gMVP		0.51

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs121908848; hg19: chr3-189456528; COSMIC: COSV99287352;