3-189789729-C-CAGAG

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_StrongBA1

The ENST00000460036.1(TP63):n.35_36insAGAG variant causes a non coding transcript exon change. The variant allele was found at a frequency of 0.329 in 1,480,580 control chromosomes in the GnomAD database, including 81,348 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.36 ( 10440 hom., cov: 0)

Exomes 𝑓: 0.32 ( 70908 hom. )

Consequence

TP63
ENST00000460036.1 non_coding_transcript_exon

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 5.67

Publications

9 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 -16 ACMG points.

BP6

Variant 3-189789729-C-CAGAG is Benign according to our data. Variant chr3-189789729-C-CAGAG is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 802034.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.536 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TP63	NM_001114980.2 link	c.-72_-71insAGAG		5_prime_UTR_variant	Exon 1 of 12	ENST00000354600.10	NP_001108452.1	Q9H3D4-2
TP63	NM_003722.5 link	c.325-18543_325-18542insAGAG		intron_variant	Intron 3 of 13	ENST00000264731.8	NP_003713.3	Q9H3D4-1A0A0S2Z4N5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TP63	ENST00000354600.10 link	c.-72_-71insAGAG		5_prime_UTR_variant	Exon 1 of 12	1	NM_001114980.2	ENSP00000346614.5		Q9H3D4-2
TP63	ENST00000264731.8 link	c.325-18543_325-18542insAGAG		intron_variant	Intron 3 of 13	1	NM_003722.5	ENSP00000264731.3		Q9H3D4-1

Frequencies

GnomAD3 genomes

AF:

0.362

AC:

54222

AN:

149706

Hom.:

10410

Cov.:

show subpopulations

Gnomad AFR

AF:

0.485

Gnomad AMI

AF:

0.349

Gnomad AMR

AF:

0.396

Gnomad ASJ

AF:

0.296

Gnomad EAS

AF:

0.552

Gnomad SAS

AF:

0.322

Gnomad FIN

AF:

0.225

Gnomad MID

AF:

0.205

Gnomad NFE

AF:

0.295

Gnomad OTH

AF:

0.342

GnomAD4 exome

AF:

0.325

AC:

432246

AN:

1330756

Hom.:

70908

Cov.:

AF XY:

0.323

AC XY:

212164

AN XY:

657698

show subpopulations

African (AFR)

AF:

0.501

AC:

14313

AN:

28584

American (AMR)

AF:

0.432

AC:

12905

AN:

29874

Ashkenazi Jewish (ASJ)

AF:

0.293

AC:

7051

AN:

24072

East Asian (EAS)

AF:

0.544

AC:

18496

AN:

34016

South Asian (SAS)

AF:

0.320

AC:

22818

AN:

71396

European-Finnish (FIN)

AF:

0.235

AC:

11690

AN:

49808

Middle Eastern (MID)

AF:

0.235

AC:

1290

AN:

5500

European-Non Finnish (NFE)

AF:

0.315

AC:

324645

AN:

1031814

Other (OTH)

AF:

0.342

AC:

19038

AN:

55692

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.462

Heterozygous variant carriers

13359

26718

40077

53436

66795

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

11102

22204

33306

44408

55510

<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:

0.363

AC:

54318

AN:

149824

Hom.:

10440

Cov.:

AF XY:

0.359

AC XY:

26240

AN XY:

73060

show subpopulations

African (AFR)

AF:

0.486

AC:

19772

AN:

40714

American (AMR)

AF:

0.396

AC:

5956

AN:

15040

Ashkenazi Jewish (ASJ)

AF:

0.296

AC:

1019

AN:

3446

East Asian (EAS)

AF:

0.553

AC:

2778

AN:

5020

South Asian (SAS)

AF:

0.321

AC:

1520

AN:

4730

European-Finnish (FIN)

AF:

0.225

AC:

2281

AN:

10148

Middle Eastern (MID)

AF:

0.212

AC:

AN:

288

European-Non Finnish (NFE)

AF:

0.295

AC:

19900

AN:

67468

Other (OTH)

AF:

0.347

AC:

718

AN:

2072

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1631

3262

4893

6524

8155

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

520

1040

1560

2080

2600

<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:

0.144

Hom.:

161

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:1

Jul 07, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Benign:1

May 28, 2019

Mendelics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

5.7

Mutation Taster

=215/85

polymorphism

(source)

Splicing

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