3-189894547-C-T

Variant summary

Our verdict is Benign. Variant got -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:5

Conservation

PhyloP100: 0.187

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id is 259123.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-189894547-C-T is described in Lovd as [Benign].

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/exons	MANE	UniProt
TP63	NM_001114980.2 linkuse as main transcript	c.*45C>T		3_prime_UTR_variant	12/12	ENST00000354600.10
TP63	NM_003722.5 linkuse as main transcript	c.*45C>T		3_prime_UTR_variant	14/14	ENST00000264731.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TP63	ENST00000264731.8 linkuse as main transcript	c.*45C>T		3_prime_UTR_variant	14/14	1	NM_003722.5	P4	Q9H3D4-1
TP63	ENST00000354600.10 linkuse as main transcript	c.*45C>T		3_prime_UTR_variant	12/12	1	NM_001114980.2	A1	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

GnomAD3 exomes

AF:

0.0555

AC:

13452

AN:

242320

Hom.:

496

AF XY:

0.0569

AC XY:

7489

AN XY:

131546

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 SAS exome

AF:

0.0228

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

Gnomad4 AFR exome

AF:

0.0149

Gnomad4 AMR exome

AF:

0.0419

Gnomad4 ASJ exome

AF:

0.0639

Gnomad4 EAS exome

AF:

0.000228

Gnomad4 SAS exome

AF:

0.0244

Gnomad4 FIN exome

AF:

0.0565

Gnomad4 NFE exome

AF:

0.0781

Gnomad4 OTH exome

AF:

0.0653

GnomAD4 genome

AF:

0.0529

AC:

8050

AN:

152186

Hom.:

291

Cov.:

AF XY:

0.0523

AC XY:

3889

AN XY:

74396

show subpopulations

Gnomad4 AFR

AF:

0.0154

Gnomad4 AMR

AF:

0.0561

Gnomad4 ASJ

AF:

0.0611

Gnomad4 EAS

AF:

0.000773

Gnomad4 SAS

AF:

0.0224

Gnomad4 FIN

AF:

0.0524

Gnomad4 NFE

AF:

0.0793

Gnomad4 OTH

AF:

0.0793

Alfa

AF:

0.0659

Hom.:

Bravo

AF:

0.0528

Asia WGS

AF:

0.0180

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

- -

TP63-Related Spectrum Disorders

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

Cadd

Benign

3.3

Dann

Benign

0.29

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over