3-189789729-C-CAGAG

Position:

• chr3-189789729-C-CAGAG

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_001114980.2(TP63):​c.-72_-71insAGAG variant causes a 5 prime UTR 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 NM_001114980.2 5_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 5.67

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id 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/exons	MANE	Protein	UniProt
TP63	NM_001114980.2	c.-72_-71insAGAG		5_prime_UTR_variant	1/12	ENST00000354600.10	NP_001108452.1
TP63	NM_003722.5	c.325-18543_325-18542insAGAG		intron_variant		ENST00000264731.8	NP_003713.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TP63	ENST00000354600	c.-72_-71insAGAG		5_prime_UTR_variant	1/12	1	NM_001114980.2	ENSP00000346614.5
TP63	ENST00000264731.8	c.325-18543_325-18542insAGAG		intron_variant		1	NM_003722.5	ENSP00000264731.3

Frequencies

GnomAD3 genomes AF: 0.362 AC: 54222 AN: 149706 Hom.: 10410 Cov.: 0

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.: 32 AF XY: 0.323 AC XY: 212164 AN XY: 657698

Gnomad4 AFR exome AF: 0.501

Gnomad4 AMR exome AF: 0.432

Gnomad4 ASJ exome AF: 0.293

Gnomad4 EAS exome AF: 0.544

Gnomad4 SAS exome AF: 0.320

Gnomad4 FIN exome AF: 0.235

Gnomad4 NFE exome AF: 0.315

Gnomad4 OTH exome AF: 0.342

GnomAD4 genome AF: 0.363 AC: 54318 AN: 149824 Hom.: 10440 Cov.: 0 AF XY: 0.359 AC XY: 26240 AN XY: 73060

Gnomad4 AFR AF: 0.486

Gnomad4 AMR AF: 0.396

Gnomad4 ASJ AF: 0.296

Gnomad4 EAS AF: 0.553

Gnomad4 SAS AF: 0.321

Gnomad4 FIN AF: 0.225

Gnomad4 NFE AF: 0.295

Gnomad4 OTH AF: 0.347

Alfa AF: 0.144 Hom.: 161

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 07, 2018

- -

Ectrodactyly, ectodermal dysplasia, and cleft lip-palate syndrome 3 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs34201045; hg19: chr3-189507518; COSMIC: COSV53195418; COSMIC: COSV53195418;