Genetic Variant TP63:c.1129+125C>T (chr3-189868841-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_003722.5(TP63):c.1129+125C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000027 in 1,483,884 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000023 ( 0 hom. )

Consequence

TP63
NM_003722.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.294

Publications

7 publications found

Variant links:

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

TP63 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.86).

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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
TP63	NM_003722.5	MANE Select	c.1129+125C>T	intron	N/A	NP_003713.3
TP63	NM_001114980.2	MANE Plus Clinical	c.847+125C>T	intron	N/A	NP_001108452.1	Q9H3D4-2
TP63	NM_001329964.2		c.1123+125C>T	intron	N/A	NP_001316893.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
TP63	ENST00000264731.8	TSL:1 MANE Select	c.1129+125C>T	intron	N/A	ENSP00000264731.3	Q9H3D4-1
TP63	ENST00000354600.10	TSL:1 MANE Plus Clinical	c.847+125C>T	intron	N/A	ENSP00000346614.5	Q9H3D4-2
TP63	ENST00000440651.6	TSL:1	c.1117+137C>T	intron	N/A	ENSP00000394337.2	Q9H3D4-11

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152024

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000225

AC:

AN:

1331860

Hom.:

AF XY:

0.00000299

AC XY:

AN XY:

669242

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30798

American (AMR)

AF:

0.00

AC:

AN:

44140

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25200

East Asian (EAS)

AF:

0.00

AC:

AN:

38794

South Asian (SAS)

AF:

0.00

AC:

AN:

82768

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50912

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5248

European-Non Finnish (NFE)

AF:

0.00000301

AC:

AN:

998110

Other (OTH)

AF:

0.00

AC:

AN:

55890

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.542

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000658

AC:

AN:

152024

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74270

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41398

American (AMR)

AF:

0.00

AC:

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10578

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

67992

Other (OTH)

AF:

0.00

AC:

AN:

2086

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

CADD

Benign

5.3

(source)

DANN

Benign

0.46

PhyloP100

-0.29

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over