rs33979049

Positions:

chr3-189866774-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The ENST00000264731.8(TP63):c.859C>T(p.Leu287=) 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 (i.e. L287L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.014 ( 23 hom., cov: 32)

Exomes 𝑓: 0.020 ( 347 hom. )

Consequence

TP63
ENST00000264731.8 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.983

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 -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 id is 259134.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-189866774-C-T is described in Lovd as [Benign].

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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 2179 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TP63	NM_003722.5 linkuse as main transcript	c.859C>T	p.Leu287=	synonymous_variant	6/14	ENST00000264731.8	NP_003713.3
TP63	NM_001114980.2 linkuse as main transcript	c.577C>T	p.Leu193=	synonymous_variant	4/12	ENST00000354600.10	NP_001108452.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TP63	ENST00000264731.8 linkuse as main transcript	c.859C>T	p.Leu287=	synonymous_variant	6/14	1	NM_003722.5	ENSP00000264731	P4	Q9H3D4-1
TP63	ENST00000354600.10 linkuse as main transcript	c.577C>T	p.Leu193=	synonymous_variant	4/12	1	NM_001114980.2	ENSP00000346614	A1	Q9H3D4-2

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

GnomAD3 exomes

AF:

0.0163

AC:

4093

AN:

251342

Hom.:

AF XY:

0.0173

AC XY:

2348

AN XY:

135824

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 SAS exome

AF:

0.0290

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

Gnomad4 AFR exome

AF:

0.00245

Gnomad4 AMR exome

AF:

0.00689

Gnomad4 ASJ exome

AF:

0.00536

Gnomad4 EAS exome

AF:

0.0227

Gnomad4 SAS exome

AF:

0.0267

Gnomad4 FIN exome

AF:

0.0143

Gnomad4 NFE exome

AF:

0.0215

Gnomad4 OTH exome

AF:

0.0180

GnomAD4 genome

AF:

0.0143

AC:

2179

AN:

152222

Hom.:

Cov.:

AF XY:

0.0139

AC XY:

1036

AN XY:

74418

show subpopulations

Gnomad4 AFR

AF:

0.00303

Gnomad4 AMR

AF:

0.00700

Gnomad4 ASJ

AF:

0.00461

Gnomad4 EAS

AF:

0.0168

Gnomad4 SAS

AF:

0.0276

Gnomad4 FIN

AF:

0.0125

Gnomad4 NFE

AF:

0.0215

Gnomad4 OTH

AF:

0.0170

Alfa

AF:

0.0174

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

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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. -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

- -

Orofacial cleft 8

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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. -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.34

CADD

Benign

7.5

DANN

Benign

0.78

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