3-189733501-C-T

Variant names:

• chr3-189733501-C-T
• rs4607088
• NM_003722.5:c.63-4239C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_003722.5(TP63):​c.63-4239C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.426 in 151,958 control chromosomes in the GnomAD database, including 14,128 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.43 (14128 hom., cov: 32)
• Consequence: TP63 NM_003722.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.44
• Publications: 4 publications found

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]

TP63 Gene-Disease associations (from GenCC):

• ADULT syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, Orphanet
• ankyloblepharon-ectodermal defects-cleft lip/palate syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, Orphanet
• ectrodactyly, ectodermal dysplasia, and cleft lip-palate syndrome 3

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• limb-mammary syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, Orphanet
• Rapp-Hodgkin syndrome

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• premature ovarian failure 21

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• split hand-foot malformation 4

  Inheritance: AD Classification: MODERATE Submitted by: Illumina
• EEC syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• split hand-foot malformation

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.52 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TP63	NM_003722.5	c.63-4239C>T		intron_variant	Intron 1 of 13	ENST00000264731.8	NP_003713.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TP63	ENST00000264731.8	c.63-4239C>T		intron_variant	Intron 1 of 13	1	NM_003722.5	ENSP00000264731.3

Frequencies

GnomAD3 genomes AF: 0.426 AC: 64674 AN: 151840 Hom.: 14101 Cov.: 32

Gnomad AFR AF: 0.525

Gnomad AMI AF: 0.154

Gnomad AMR AF: 0.459

Gnomad ASJ AF: 0.379

Gnomad EAS AF: 0.469

Gnomad SAS AF: 0.370

Gnomad FIN AF: 0.365

Gnomad MID AF: 0.417

Gnomad NFE AF: 0.374

Gnomad OTH AF: 0.439

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.426 AC: 64741 AN: 151958 Hom.: 14128 Cov.: 32 AF XY: 0.423 AC XY: 31388 AN XY: 74282

African (AFR) AF: 0.526 AC: 21782 AN: 41442

American (AMR) AF: 0.459 AC: 6998 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.379 AC: 1316 AN: 3470

East Asian (EAS) AF: 0.469 AC: 2420 AN: 5162

South Asian (SAS) AF: 0.369 AC: 1778 AN: 4822

European-Finnish (FIN) AF: 0.365 AC: 3851 AN: 10542

Middle Eastern (MID) AF: 0.421 AC: 123 AN: 292

European-Non Finnish (NFE) AF: 0.374 AC: 25416 AN: 67944

Other (OTH) AF: 0.435 AC: 917 AN: 2110

Alfa AF: 0.393 Hom.: 13990

Bravo AF: 0.438

Asia WGS AF: 0.427 AC: 1488 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.77
DANN	Benign	0.60
PhyloP100		-1.4
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs4607088; hg19: chr3-189451290;