rs1913720

Variant names:

• chr3-189857038-A-G
• rs1913720
• NM_003722.5:c.580-7194A>G

Variant summary

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

The NM_003722.5(TP63):​c.580-7194A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.422 in 151,870 control chromosomes in the GnomAD database, including 13,937 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 0.42 (13937 hom., cov: 32)
• Consequence: TP63 NM_003722.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0890
• Publications: 2 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=-0.93).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.516 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TP63	NM_003722.5	c.580-7194A>G		intron_variant	Intron 4 of 13	ENST00000264731.8	NP_003713.3
TP63	NM_001114980.2	c.298-7194A>G		intron_variant	Intron 2 of 11	ENST00000354600.10	NP_001108452.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TP63	ENST00000264731.8	c.580-7194A>G		intron_variant	Intron 4 of 13	1	NM_003722.5	ENSP00000264731.3
TP63	ENST00000354600.10	c.298-7194A>G		intron_variant	Intron 2 of 11	1	NM_001114980.2	ENSP00000346614.5

Frequencies

GnomAD3 genomes AF: 0.423 AC: 64141 AN: 151752 Hom.: 13941 Cov.: 32

Gnomad AFR AF: 0.523

Gnomad AMI AF: 0.324

Gnomad AMR AF: 0.369

Gnomad ASJ AF: 0.367

Gnomad EAS AF: 0.375

Gnomad SAS AF: 0.300

Gnomad FIN AF: 0.359

Gnomad MID AF: 0.481

Gnomad NFE AF: 0.400

Gnomad OTH AF: 0.430

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

GnomAD4 genome AF: 0.422 AC: 64146 AN: 151870 Hom.: 13937 Cov.: 32 AF XY: 0.416 AC XY: 30893 AN XY: 74256

African (AFR) AF: 0.522 AC: 21643 AN: 41442

American (AMR) AF: 0.369 AC: 5628 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.367 AC: 1270 AN: 3462

East Asian (EAS) AF: 0.375 AC: 1941 AN: 5178

South Asian (SAS) AF: 0.301 AC: 1453 AN: 4830

European-Finnish (FIN) AF: 0.359 AC: 3789 AN: 10550

Middle Eastern (MID) AF: 0.473 AC: 139 AN: 294

European-Non Finnish (NFE) AF: 0.399 AC: 27089 AN: 67822

Other (OTH) AF: 0.426 AC: 899 AN: 2110

Alfa AF: 0.408 Hom.: 1605

Bravo AF: 0.431

Asia WGS AF: 0.312 AC: 1085 AN: 3468

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	1.4
DANN	Benign	0.69
PhyloP100		0.089
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1913720; hg19: chr3-189574827;