chr3-189699198-C-T

Variant names:

• chr3-189699198-C-T
• rs12696596
• NM_003722.5:c.63-38542C>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.63-38542C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.347 in 151,990 control chromosomes in the GnomAD database, including 9,784 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 0.35 (9784 hom., cov: 33)
• Consequence: TP63 NM_003722.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.193
• 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=-0.89).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.624 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TP63	NM_003722.5	c.63-38542C>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.63-38542C>T		intron_variant	Intron 1 of 13	1	NM_003722.5	ENSP00000264731.3

Frequencies

GnomAD3 genomes AF: 0.347 AC: 52716 AN: 151872 Hom.: 9789 Cov.: 33

Gnomad AFR AF: 0.232

Gnomad AMI AF: 0.523

Gnomad AMR AF: 0.318

Gnomad ASJ AF: 0.309

Gnomad EAS AF: 0.643

Gnomad SAS AF: 0.464

Gnomad FIN AF: 0.418

Gnomad MID AF: 0.294

Gnomad NFE AF: 0.382

Gnomad OTH AF: 0.348

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

GnomAD4 genome AF: 0.347 AC: 52729 AN: 151990 Hom.: 9784 Cov.: 33 AF XY: 0.351 AC XY: 26039 AN XY: 74262

African (AFR) AF: 0.231 AC: 9601 AN: 41486

American (AMR) AF: 0.317 AC: 4843 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.309 AC: 1069 AN: 3462

East Asian (EAS) AF: 0.642 AC: 3313 AN: 5158

South Asian (SAS) AF: 0.463 AC: 2230 AN: 4812

European-Finnish (FIN) AF: 0.418 AC: 4422 AN: 10572

Middle Eastern (MID) AF: 0.310 AC: 91 AN: 294

European-Non Finnish (NFE) AF: 0.382 AC: 25946 AN: 67934

Other (OTH) AF: 0.351 AC: 737 AN: 2102

Alfa AF: 0.358 Hom.: 1314

Bravo AF: 0.333

Asia WGS AF: 0.516 AC: 1794 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	7.4
DANN	Benign	0.67
PhyloP100		-0.19
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: rs12696596; hg19: chr3-189416987;