rs1920267

Variant names:

• chr3-189653199-T-C
• rs1920267
• NM_003722.5:c.62+21622T>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.62+21622T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.896 in 152,194 control chromosomes in the GnomAD database, including 62,503 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 0.90 (62503 hom., cov: 31)
• Consequence: TP63 NM_003722.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.410
• 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=-0.91).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.978 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TP63	NM_003722.5	c.62+21622T>C		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.62+21622T>C		intron_variant	Intron 1 of 13	1	NM_003722.5	ENSP00000264731.3

Frequencies

GnomAD3 genomes AF: 0.896 AC: 136316 AN: 152076 Hom.: 62473 Cov.: 31

Gnomad AFR AF: 0.684

Gnomad AMI AF: 0.992

Gnomad AMR AF: 0.945

Gnomad ASJ AF: 0.946

Gnomad EAS AF: 0.955

Gnomad SAS AF: 0.961

Gnomad FIN AF: 0.999

Gnomad MID AF: 0.981

Gnomad NFE AF: 0.984

Gnomad OTH AF: 0.923

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

GnomAD4 genome AF: 0.896 AC: 136396 AN: 152194 Hom.: 62503 Cov.: 31 AF XY: 0.900 AC XY: 66997 AN XY: 74408

African (AFR) AF: 0.684 AC: 28367 AN: 41474

American (AMR) AF: 0.946 AC: 14470 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.946 AC: 3281 AN: 3470

East Asian (EAS) AF: 0.955 AC: 4936 AN: 5168

South Asian (SAS) AF: 0.962 AC: 4635 AN: 4820

European-Finnish (FIN) AF: 0.999 AC: 10601 AN: 10616

Middle Eastern (MID) AF: 0.983 AC: 289 AN: 294

European-Non Finnish (NFE) AF: 0.984 AC: 66960 AN: 68026

Other (OTH) AF: 0.924 AC: 1952 AN: 2112

Alfa AF: 0.933 Hom.: 8336

Bravo AF: 0.883

Asia WGS AF: 0.931 AC: 3236 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.51
DANN	Benign	0.64
PhyloP100		-0.41
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: rs1920267; hg19: chr3-189370988;