3-189789729-C-CAG

Variant names:

• chr3-189789729-C-CAG
• rs34201045
• ENST00000460036.1:n.35_36insAG

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The ENST00000460036.1(TP63):​n.35_36insAG variant causes a non coding transcript exon change. The variant allele was found at a frequency of 0.0817 in 1,482,242 control chromosomes in the GnomAD database, including 5,607 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.070 (506 hom., cov: 0)
  • Exomes 𝑓: 0.083 (5101 hom.)
• Consequence: TP63 ENST00000460036.1 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 5.67
• Publications: 9 publications found

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

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP6: Variant 3-189789729-C-CAG is Benign according to our data. Variant chr3-189789729-C-CAG is described in ClinVar as Benign. ClinVar VariationId is 1241414.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.122 is higher than 0.05.

Transcripts

RefSeq

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

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.0698 AC: 10456 AN: 149872 Hom.: 506 Cov.: 0

Gnomad AFR AF: 0.0165

Gnomad AMI AF: 0.0111

Gnomad AMR AF: 0.127

Gnomad ASJ AF: 0.0873

Gnomad EAS AF: 0.00516

Gnomad SAS AF: 0.102

Gnomad FIN AF: 0.121

Gnomad MID AF: 0.0929

Gnomad NFE AF: 0.0836

Gnomad OTH AF: 0.0794

GnomAD4 exome AF: 0.0831 AC: 110704 AN: 1332252 Hom.: 5101 Cov.: 32 AF XY: 0.0835 AC XY: 54992 AN XY: 658412

African (AFR) AF: 0.0142 AC: 407 AN: 28640

American (AMR) AF: 0.175 AC: 5229 AN: 29890

Ashkenazi Jewish (ASJ) AF: 0.0856 AC: 2062 AN: 24102

East Asian (EAS) AF: 0.00252 AC: 86 AN: 34064

South Asian (SAS) AF: 0.105 AC: 7527 AN: 71482

European-Finnish (FIN) AF: 0.113 AC: 5637 AN: 49820

Middle Eastern (MID) AF: 0.112 AC: 618 AN: 5502

European-Non Finnish (NFE) AF: 0.0820 AC: 84720 AN: 1032994

Other (OTH) AF: 0.0792 AC: 4418 AN: 55758

GnomAD4 genome AF: 0.0697 AC: 10460 AN: 149990 Hom.: 506 Cov.: 0 AF XY: 0.0725 AC XY: 5301 AN XY: 73150

African (AFR) AF: 0.0165 AC: 673 AN: 40782

American (AMR) AF: 0.126 AC: 1906 AN: 15068

Ashkenazi Jewish (ASJ) AF: 0.0873 AC: 301 AN: 3448

East Asian (EAS) AF: 0.00537 AC: 27 AN: 5026

South Asian (SAS) AF: 0.102 AC: 485 AN: 4732

European-Finnish (FIN) AF: 0.121 AC: 1228 AN: 10170

Middle Eastern (MID) AF: 0.0868 AC: 25 AN: 288

European-Non Finnish (NFE) AF: 0.0836 AC: 5640 AN: 67500

Other (OTH) AF: 0.0795 AC: 165 AN: 2076

Alfa AF: 0.0548 Hom.: 161

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Sep 11, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		5.7
Mutation Taster		=167/133	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs34201045; hg19: chr3-189507518; COSMIC: COSV53198297;