3-189886371-T-C

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.1350-23T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.766 in 1,611,378 control chromosomes in the GnomAD database, including 475,797 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.74 ( 42417 hom., cov: 32)

Exomes 𝑓: 0.77 ( 433380 hom. )

Consequence

TP63
NM_003722.5 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.0850

Publications

17 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=-0.88).

BP6

Variant 3-189886371-T-C is Benign according to our data. Variant chr3-189886371-T-C is described in ClinVar as Benign. ClinVar VariationId is 259127.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.783 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TP63	NM_003722.5 link	c.1350-23T>C		intron_variant	Intron 10 of 13	ENST00000264731.8	NP_003713.3
TP63	NM_001114980.2 link	c.1068-23T>C		intron_variant	Intron 8 of 11	ENST00000354600.10	NP_001108452.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TP63	ENST00000264731.8 link	c.1350-23T>C		intron_variant	Intron 10 of 13	1	NM_003722.5	ENSP00000264731.3
TP63	ENST00000354600.10 link	c.1068-23T>C		intron_variant	Intron 8 of 11	1	NM_001114980.2	ENSP00000346614.5

Frequencies

GnomAD3 genomes

AF:

0.744

AC:

113060

AN:

151954

Hom.:

42399

Cov.:

show subpopulations

Gnomad AFR

AF:

0.748

Gnomad AMI

AF:

0.755

Gnomad AMR

AF:

0.624

Gnomad ASJ

AF:

0.692

Gnomad EAS

AF:

0.605

Gnomad SAS

AF:

0.714

Gnomad FIN

AF:

0.704

Gnomad MID

AF:

0.902

Gnomad NFE

AF:

0.789

Gnomad OTH

AF:

0.764

GnomAD2 exomes

AF:

0.711

AC:

178228

AN:

250778

AF XY:

0.723

show subpopulations

Gnomad AFR exome

AF:

0.746

Gnomad AMR exome

AF:

0.501

Gnomad ASJ exome

AF:

0.686

Gnomad EAS exome

AF:

0.598

Gnomad FIN exome

AF:

0.696

Gnomad NFE exome

AF:

0.789

Gnomad OTH exome

AF:

0.737

GnomAD4 exome

AF:

0.768

AC:

1120877

AN:

1459304

Hom.:

433380

Cov.:

AF XY:

0.768

AC XY:

557986

AN XY:

726078

show subpopulations

African (AFR)

AF:

0.744

AC:

24883

AN:

33438

American (AMR)

AF:

0.514

AC:

22971

AN:

44708

Ashkenazi Jewish (ASJ)

AF:

0.683

AC:

17837

AN:

26116

East Asian (EAS)

AF:

0.635

AC:

25197

AN:

39654

South Asian (SAS)

AF:

0.718

AC:

61850

AN:

86134

European-Finnish (FIN)

AF:

0.703

AC:

37249

AN:

52984

Middle Eastern (MID)

AF:

0.847

AC:

4880

AN:

5762

European-Non Finnish (NFE)

AF:

0.793

AC:

880050

AN:

1110190

Other (OTH)

AF:

0.762

AC:

45960

AN:

60318

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

12819

25637

38456

51274

64093

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

20554

41108

61662

82216

102770

<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:

0.744

AC:

113118

AN:

152074

Hom.:

42417

Cov.:

AF XY:

0.735

AC XY:

54599

AN XY:

74318

show subpopulations

African (AFR)

AF:

0.748

AC:

31014

AN:

41482

American (AMR)

AF:

0.623

AC:

9505

AN:

15264

Ashkenazi Jewish (ASJ)

AF:

0.692

AC:

2401

AN:

3470

East Asian (EAS)

AF:

0.606

AC:

3128

AN:

5164

South Asian (SAS)

AF:

0.714

AC:

3445

AN:

4822

European-Finnish (FIN)

AF:

0.704

AC:

7444

AN:

10580

Middle Eastern (MID)

AF:

0.895

AC:

263

AN:

294

European-Non Finnish (NFE)

AF:

0.789

AC:

53627

AN:

67974

Other (OTH)

AF:

0.759

AC:

1602

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1491

2982

4473

5964

7455

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

850

1700

2550

3400

4250

<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:

0.717

Hom.:

7507

Bravo

AF:

0.736

Asia WGS

AF:

0.655

AC:

2283

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

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

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.88

CADD

Benign

5.6

(source)

DANN

Benign

0.67

PhyloP100

0.085

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