rs1452651956

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PP2PP3BS2

The NM_003722.5(TP63):c.61C>T(p.Arg21Cys) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000013 in 1,612,586 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/2 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R21H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000013 ( 0 hom. )

Consequence

TP63
NM_003722.5 missense, splice_region

Scores

Splicing: ADA: 0.9893

Clinical Significance

Uncertain significance criteria provided, single submitter U:3

Conservation

PhyloP100: 5.24

Publications

0 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, Labcorp Genetics (formerly Invitae), Ambry Genetics
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)
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.

PP2

Missense variant in the TP63 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 73 curated pathogenic missense variants (we use a threshold of 10). The gene has 15 curated benign missense variants. Gene score misZ: 2.2077 (below the threshold of 3.09). Trascript score misZ: 3.5096 (above the threshold of 3.09). GenCC associations: The gene is linked to Rapp-Hodgkin syndrome, ADULT syndrome, premature ovarian failure 21, limb-mammary syndrome, ectrodactyly, ectodermal dysplasia, and cleft lip-palate syndrome 3, ankyloblepharon-ectodermal defects-cleft lip/palate syndrome, EEC syndrome, split hand-foot malformation, split hand-foot malformation 4.

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. No scorers claiming Benign.

BS2

High AC in GnomAdExome4 at 19 AD gene.

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	HGVSp	Effect	Exon Rank	Protein	UniProt
TP63	NM_003722.5	MANE Select	c.61C>T	p.Arg21Cys	missense splice_region	Exon 1 of 14	NP_003713.3
TP63	NM_001329148.2		c.61C>T	p.Arg21Cys	missense splice_region	Exon 1 of 14	NP_001316077.1	A0A0S2Z4N6
TP63	NM_001114978.2		c.61C>T	p.Arg21Cys	missense splice_region	Exon 1 of 13	NP_001108450.1	Q9H3D4-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TP63	ENST00000264731.8	TSL:1 MANE Select	c.61C>T	p.Arg21Cys	missense splice_region	Exon 1 of 14	ENSP00000264731.3	Q9H3D4-1
TP63	ENST00000440651.6	TSL:1	c.61C>T	p.Arg21Cys	missense splice_region	Exon 1 of 14	ENSP00000394337.2	Q9H3D4-11
TP63	ENST00000392460.7	TSL:1	c.61C>T	p.Arg21Cys	missense splice_region	Exon 1 of 13	ENSP00000376253.3	Q9H3D4-3

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

152088

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000656

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000208

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000119

AC:

AN:

251134

AF XY:

0.00000737

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000130

AC:

AN:

1460498

Hom.:

Cov.:

AF XY:

0.0000165

AC XY:

AN XY:

726630

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33392

American (AMR)

AF:

0.00

AC:

AN:

44668

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26066

East Asian (EAS)

AF:

0.000151

AC:

AN:

39668

South Asian (SAS)

AF:

0.000116

AC:

AN:

86240

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53392

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5752

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1111028

Other (OTH)

AF:

0.0000166

AC:

AN:

60292

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.462

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:

0.0000132

AC:

AN:

152088

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74268

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41426

American (AMR)

AF:

0.0000656

AC:

AN:

15252

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.000208

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68018

Other (OTH)

AF:

0.00

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.0000371

Hom.:

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Ectrodactyly, ectodermal dysplasia, and cleft lip-palate syndrome 3 (1)

Orofacial cleft 8 (1)

TP63-Related Spectrum Disorders (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Pathogenic

0.32

BayesDel_noAF

Pathogenic

0.40

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.38

Eigen

Uncertain

0.58

Eigen_PC

Uncertain

0.65

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.93

M_CAP

Pathogenic

0.35

MetaRNN

Pathogenic

0.76

MetaSVM

Pathogenic

1.1

MutationAssessor

Benign

1.2

PhyloP100

5.2

PrimateAI

Pathogenic

0.79

PROVEAN

Benign

-0.53

REVEL

Pathogenic

0.71

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0020

Polyphen

1.0

Vest4

0.84

MutPred

0.54

Gain of sheet (P = 0.0085)

MVP

0.93

MPC

1.3

ClinPred

0.81

GERP RS

5.7

PromoterAI

-0.045

Neutral

(source)

Varity_R

0.40

gMVP

0.60

Mutation Taster

=44/56

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.99

dbscSNV1_RF

Pathogenic

0.74

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over