rs33979049

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_003722.5(TP63):c.859C>T(p.Leu287Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0197 in 1,613,978 control chromosomes in the GnomAD database, including 370 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.014 ( 23 hom., cov: 32)

Exomes 𝑓: 0.020 ( 347 hom. )

Consequence

TP63
NM_003722.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 0.983

Publications

12 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: 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

TP63 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.34).

BP6

Variant 3-189866774-C-T is Benign according to our data. Variant chr3-189866774-C-T is described in ClinVar as Benign. ClinVar VariationId is 259134.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.983 with no splicing effect.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0143 (2179/152222) while in subpopulation SAS AF = 0.0276 (133/4818). AF 95% confidence interval is 0.0238. There are 23 homozygotes in GnomAd4. There are 1036 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 2179 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TP63	NM_003722.5 link	c.859C>T	p.Leu287Leu	synonymous_variant	Exon 6 of 14	ENST00000264731.8	NP_003713.3
TP63	NM_001114980.2 link	c.577C>T	p.Leu193Leu	synonymous_variant	Exon 4 of 12	ENST00000354600.10	NP_001108452.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TP63	ENST00000264731.8 link	c.859C>T	p.Leu287Leu	synonymous_variant	Exon 6 of 14	1	NM_003722.5	ENSP00000264731.3
TP63	ENST00000354600.10 link	c.577C>T	p.Leu193Leu	synonymous_variant	Exon 4 of 12	1	NM_001114980.2	ENSP00000346614.5

Frequencies

GnomAD3 genomes

AF:

0.0143

AC:

2181

AN:

152104

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00304

Gnomad AMI

AF:

0.0868

Gnomad AMR

AF:

0.00701

Gnomad ASJ

AF:

0.00461

Gnomad EAS

AF:

0.0168

Gnomad SAS

AF:

0.0278

Gnomad FIN

AF:

0.0125

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0215

Gnomad OTH

AF:

0.0177

GnomAD2 exomes

AF:

0.0163

AC:

4093

AN:

251342

AF XY:

0.0173

show subpopulations

Gnomad AFR exome

AF:

0.00289

Gnomad AMR exome

AF:

0.00648

Gnomad ASJ exome

AF:

0.00526

Gnomad EAS exome

AF:

0.0120

Gnomad FIN exome

AF:

0.0141

Gnomad NFE exome

AF:

0.0200

Gnomad OTH exome

AF:

0.0132

GnomAD4 exome

AF:

0.0202

AC:

29556

AN:

1461756

Hom.:

347

Cov.:

AF XY:

0.0205

AC XY:

14924

AN XY:

727170

show subpopulations

African (AFR)

AF:

0.00245

AC:

AN:

33472

American (AMR)

AF:

0.00689

AC:

308

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00536

AC:

140

AN:

26132

East Asian (EAS)

AF:

0.0227

AC:

901

AN:

39686

South Asian (SAS)

AF:

0.0267

AC:

2304

AN:

86250

European-Finnish (FIN)

AF:

0.0143

AC:

764

AN:

53418

Middle Eastern (MID)

AF:

0.00347

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0215

AC:

23948

AN:

1111918

Other (OTH)

AF:

0.0180

AC:

1089

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

1593

3186

4780

6373

7966

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

910

1820

2730

3640

4550

<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:

0.0143

AC:

2179

AN:

152222

Hom.:

Cov.:

AF XY:

0.0139

AC XY:

1036

AN XY:

74418

show subpopulations

African (AFR)

AF:

0.00303

AC:

126

AN:

41546

American (AMR)

AF:

0.00700

AC:

107

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00461

AC:

AN:

3472

East Asian (EAS)

AF:

0.0168

AC:

AN:

5170

South Asian (SAS)

AF:

0.0276

AC:

133

AN:

4818

European-Finnish (FIN)

AF:

0.0125

AC:

133

AN:

10598

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0215

AC:

1462

AN:

68008

Other (OTH)

AF:

0.0170

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

109

219

328

438

547

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

112

140

<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:

0.0180

Hom.:

Bravo

AF:

0.0131

Asia WGS

AF:

0.0180

AC:

AN:

3478

EpiCase

AF:

0.0198

EpiControl

AF:

0.0205

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

TP63-Related Spectrum Disorders

Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Orofacial cleft 8

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Ectrodactyly, ectodermal dysplasia, and cleft lip-palate syndrome 3

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.34

CADD

Benign

7.5

(source)

DANN

Benign

0.78

PhyloP100

0.98

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over