rs1920266

Variant names:

• chr3-189653225-C-A
• rs1920266
• NM_003722.5:c.62+21648C>A

Your query was ambiguous. Multiple possible variants found:

• chr3-189653225-C-A
• chr3-189653225-C-G

Variant summary

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

The ENST00000264731.8(TP63):​c.62+21648C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.456 in 152,066 control chromosomes in the GnomAD database, including 16,174 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 0.46 (16174 hom., cov: 32)
• Consequence: TP63 ENST00000264731.8 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.40
• Publications: 8 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 (EAS) allele frequency at 95% confidence interval = 0.663 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000264731.8. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TP63	NM_003722.5	MANE Select	c.62+21648C>A		intron	N/A	NP_003713.3
	TP63	NM_001329964.2		c.56+55987C>A		intron	N/A	NP_001316893.1
	TP63	NM_001329148.2		c.62+21648C>A		intron	N/A	NP_001316077.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TP63	ENST00000264731.8	TSL:1 MANE Select	c.62+21648C>A		intron	N/A	ENSP00000264731.3
	TP63	ENST00000440651.6	TSL:1	c.62+21648C>A		intron	N/A	ENSP00000394337.2
	TP63	ENST00000392460.7	TSL:1	c.62+21648C>A		intron	N/A	ENSP00000376253.3

Frequencies

GnomAD3 genomes AF: 0.456 AC: 69273 AN: 151948 Hom.: 16171 Cov.: 32

Gnomad AFR AF: 0.438

Gnomad AMI AF: 0.643

Gnomad AMR AF: 0.359

Gnomad ASJ AF: 0.419

Gnomad EAS AF: 0.682

Gnomad SAS AF: 0.449

Gnomad FIN AF: 0.535

Gnomad MID AF: 0.294

Gnomad NFE AF: 0.460

Gnomad OTH AF: 0.418

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

GnomAD4 genome AF: 0.456 AC: 69304 AN: 152066 Hom.: 16174 Cov.: 32 AF XY: 0.458 AC XY: 34054 AN XY: 74336

African (AFR) AF: 0.438 AC: 18175 AN: 41474

American (AMR) AF: 0.359 AC: 5489 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.419 AC: 1454 AN: 3468

East Asian (EAS) AF: 0.682 AC: 3512 AN: 5152

South Asian (SAS) AF: 0.449 AC: 2164 AN: 4820

European-Finnish (FIN) AF: 0.535 AC: 5664 AN: 10582

Middle Eastern (MID) AF: 0.293 AC: 86 AN: 294

European-Non Finnish (NFE) AF: 0.461 AC: 31298 AN: 67964

Other (OTH) AF: 0.416 AC: 877 AN: 2110

Alfa AF: 0.446 Hom.: 13091

Bravo AF: 0.442

Asia WGS AF: 0.520 AC: 1811 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.14
DANN	Benign	0.38
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: rs1920266; hg19: chr3-189371014;