3-189631577-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PP2 PP3_Moderate

The NM_003722.5(TP63):c.62G>A(p.Arg21His) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000164 in 1,460,524 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/2 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R21C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: TP63 NM_003722.5 missense, splice_region
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 6.64

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 Uncertain_significance. Variant got 3 ACMG points.

• PP2: Missense variant where missense usually causes diseases, TP63
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TP63	NM_003722.5	c.62G>A	p.Arg21His	missense_variant, splice_region_variant	1/14	ENST00000264731.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TP63	ENST00000264731.8	c.62G>A	p.Arg21His	missense_variant, splice_region_variant	1/14	1	NM_003722.5	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000119 AC: 3 AN: 251114 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135714

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000164 AC: 24 AN: 1460524 Hom.: 0 Cov.: 33 AF XY: 0.0000179 AC XY: 13 AN XY: 726640

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000672

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000162

Gnomad4 OTH exome AF: 0.0000332

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

TP63-Related Spectrum Disorders Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 11, 2023

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 21 of the TP63 protein (p.Arg21His). This variant also falls at the last nucleotide of exon 1, which is part of the consensus splice site for this exon. This variant is present in population databases (rs766583971, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with TP63-related conditions. ClinVar contains an entry for this variant (Variation ID: 1510128). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Ankyloblepharon-ectodermal defects-cleft lip/palate syndrome;C1785148:Rapp-Hodgkin ectodermal dysplasia syndrome;C1851878:Orofacial cleft 8;C1854442:Split hand-foot malformation 4;C1858562:Ectrodactyly, ectodermal dysplasia, and cleft lip-palate syndrome 3;C1863204:ADULT syndrome;C1863753:Limb-mammary syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 05, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Pathogenic	0.24
Cadd	Pathogenic	35
Dann	Uncertain	1.0
DEOGEN2	Benign	0.37	T;.;.;.;.
Eigen	Uncertain	0.61
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.91	D;D;D;D;D
M_CAP	Pathogenic	0.34	D
MetaRNN	Uncertain	0.66	D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.2	L;L;L;L;L
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-0.23	N;N;N;N;N
REVEL	Uncertain	0.60
Sift	Uncertain	0.0040	D;D;D;D;D
Sift4G	Uncertain	0.019	D;D;D;D;D
Polyphen		0.99	D;D;D;D;.
Vest4		0.75
MutPred		0.41		Gain of glycosylation at Y18 (P = 0.0275);Gain of glycosylation at Y18 (P = 0.0275);Gain of glycosylation at Y18 (P = 0.0275);Gain of glycosylation at Y18 (P = 0.0275);Gain of glycosylation at Y18 (P = 0.0275);
MVP		0.84
MPC		1.1
ClinPred		0.81	D
GERP RS		5.7
Varity_R		0.28
gMVP		0.53

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.96

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

Publications

LitVar

Other links and lift over

dbSNP: rs766583971; hg19: chr3-189349366; COSMIC: COSV53198919;