3-189894547-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_003722.5(TP63):c.*45C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0673 in 1,605,380 control chromosomes in the GnomAD database, including 4,123 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.053 ( 291 hom., cov: 32)

Exomes 𝑓: 0.069 ( 3832 hom. )

Consequence

TP63
NM_003722.5 3_prime_UTR

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.187

Publications

5 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.83).

BP6

Variant 3-189894547-C-T is Benign according to our data. Variant chr3-189894547-C-T is described in ClinVar as Benign. ClinVar VariationId is 259123.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0775 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TP63	NM_003722.5 link	c.*45C>T		3_prime_UTR_variant	Exon 14 of 14	ENST00000264731.8	NP_003713.3	Q9H3D4-1A0A0S2Z4N5
TP63	NM_001114980.2 link	c.*45C>T		3_prime_UTR_variant	Exon 12 of 12	ENST00000354600.10	NP_001108452.1	Q9H3D4-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TP63	ENST00000264731.8 link	c.*45C>T		3_prime_UTR_variant	Exon 14 of 14	1	NM_003722.5	ENSP00000264731.3		Q9H3D4-1
TP63	ENST00000354600.10 link	c.*45C>T		3_prime_UTR_variant	Exon 12 of 12	1	NM_001114980.2	ENSP00000346614.5		Q9H3D4-2

Frequencies

GnomAD3 genomes

AF:

0.0530

AC:

8054

AN:

152068

Hom.:

291

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0154

Gnomad AMI

AF:

0.0769

Gnomad AMR

AF:

0.0561

Gnomad ASJ

AF:

0.0611

Gnomad EAS

AF:

0.000771

Gnomad SAS

AF:

0.0222

Gnomad FIN

AF:

0.0524

Gnomad MID

AF:

0.155

Gnomad NFE

AF:

0.0793

Gnomad OTH

AF:

0.0811

GnomAD2 exomes

AF:

0.0555

AC:

13452

AN:

242320

AF XY:

0.0569

show subpopulations

Gnomad AFR exome

AF:

0.0140

Gnomad AMR exome

AF:

0.0402

Gnomad ASJ exome

AF:

0.0651

Gnomad EAS exome

AF:

0.000166

Gnomad FIN exome

AF:

0.0546

Gnomad NFE exome

AF:

0.0829

Gnomad OTH exome

AF:

0.0684

GnomAD4 exome

AF:

0.0688

AC:

99921

AN:

1453194

Hom.:

3832

Cov.:

AF XY:

0.0679

AC XY:

49105

AN XY:

722962

show subpopulations

African (AFR)

AF:

0.0149

AC:

496

AN:

33368

American (AMR)

AF:

0.0419

AC:

1867

AN:

44540

Ashkenazi Jewish (ASJ)

AF:

0.0639

AC:

1666

AN:

26074

East Asian (EAS)

AF:

0.000228

AC:

AN:

39560

South Asian (SAS)

AF:

0.0244

AC:

2094

AN:

85834

European-Finnish (FIN)

AF:

0.0565

AC:

2815

AN:

49858

Middle Eastern (MID)

AF:

0.0928

AC:

396

AN:

4266

European-Non Finnish (NFE)

AF:

0.0781

AC:

86656

AN:

1109608

Other (OTH)

AF:

0.0653

AC:

3922

AN:

60086

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

5108

10216

15323

20431

25539

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3096

6192

9288

12384

15480

<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:

0.0529

AC:

8050

AN:

152186

Hom.:

291

Cov.:

AF XY:

0.0523

AC XY:

3889

AN XY:

74396

show subpopulations

African (AFR)

AF:

0.0154

AC:

640

AN:

41532

American (AMR)

AF:

0.0561

AC:

857

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.0611

AC:

212

AN:

3472

East Asian (EAS)

AF:

0.000773

AC:

AN:

5176

South Asian (SAS)

AF:

0.0224

AC:

108

AN:

4824

European-Finnish (FIN)

AF:

0.0524

AC:

555

AN:

10586

Middle Eastern (MID)

AF:

0.153

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0793

AC:

5392

AN:

68000

Other (OTH)

AF:

0.0793

AC:

167

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

373

746

1120

1493

1866

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

180

270

360

450

<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:

0.0682

Hom.:

134

Bravo

AF:

0.0528

Asia WGS

AF:

0.0180

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

TP63-Related Spectrum Disorders

Benign:1

Jan 13, 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. -

Orofacial cleft 8

Benign:1

Jan 13, 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 13, 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

-0.83

CADD

Benign

3.3

(source)

DANN

Benign

0.29

PhyloP100

0.19

Mutation Taster

=94/6

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

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over