rs9865857

Variant names:

• chr3-189870261-A-C
• rs9865857
• NM_003722.5:c.1212+855A>C

Variant summary

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

The NM_003722.5(TP63):​c.1212+855A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.443 in 151,968 control chromosomes in the GnomAD database, including 15,899 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 0.44 (15899 hom., cov: 31)
• Consequence: TP63 NM_003722.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.640
• 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: Orphanet, G2P
• ankyloblepharon-ectodermal defects-cleft lip/palate syndrome

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

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

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

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

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• TP63-related ectodermal dysplasia spectrum with limb and orofacial malformations

  Inheritance: AD Classification: STRONG Submitted by: PanelApp Australia
• 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=-0.9).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.604 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003722.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TP63	NM_003722.5	MANE Select	c.1212+855A>C		intron	N/A	NP_003713.3
	TP63	NM_001114980.2	MANE Plus Clinical	c.930+855A>C		intron	N/A	NP_001108452.1	Q9H3D4-2
	TP63	NM_001329964.2		c.1206+855A>C		intron	N/A	NP_001316893.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TP63	ENST00000264731.8	TSL:1 MANE Select	c.1212+855A>C		intron	N/A	ENSP00000264731.3	Q9H3D4-1
	TP63	ENST00000354600.10	TSL:1 MANE Plus Clinical	c.930+855A>C		intron	N/A	ENSP00000346614.5	Q9H3D4-2
	TP63	ENST00000440651.6	TSL:1	c.1200+855A>C		intron	N/A	ENSP00000394337.2	Q9H3D4-11

Frequencies

GnomAD3 genomes AF: 0.443 AC: 67291 AN: 151852 Hom.: 15886 Cov.: 31

Gnomad AFR AF: 0.610

Gnomad AMI AF: 0.248

Gnomad AMR AF: 0.380

Gnomad ASJ AF: 0.355

Gnomad EAS AF: 0.345

Gnomad SAS AF: 0.274

Gnomad FIN AF: 0.354

Gnomad MID AF: 0.513

Gnomad NFE AF: 0.396

Gnomad OTH AF: 0.453

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

GnomAD4 genome AF: 0.443 AC: 67328 AN: 151968 Hom.: 15899 Cov.: 31 AF XY: 0.434 AC XY: 32235 AN XY: 74288

African (AFR) AF: 0.610 AC: 25271 AN: 41436

American (AMR) AF: 0.379 AC: 5786 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.355 AC: 1232 AN: 3468

East Asian (EAS) AF: 0.345 AC: 1784 AN: 5170

South Asian (SAS) AF: 0.275 AC: 1321 AN: 4812

European-Finnish (FIN) AF: 0.354 AC: 3735 AN: 10560

Middle Eastern (MID) AF: 0.500 AC: 147 AN: 294

European-Non Finnish (NFE) AF: 0.396 AC: 26880 AN: 67954

Other (OTH) AF: 0.450 AC: 946 AN: 2102

Alfa AF: 0.411 Hom.: 1673

Bravo AF: 0.456

Asia WGS AF: 0.290 AC: 1012 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	4.2
DANN	Benign	0.79
PhyloP100		0.64
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: rs9865857; hg19: chr3-189588050;