chr3-189789729-C-CAGTG

Variant names:

• chr3-189789729-C-CAGTG
• rs34201045
• NM_001114980.2:c.-72_-71insAGTG

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001114980.2(TP63):​c.-72_-71insAGTG variant causes a 5 prime UTR change. The variant allele was found at a frequency of 0.00000375 in 1,332,692 control chromosomes in the GnomAD database, with no homozygous occurrence. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 0)
  • Exomes 𝑓: 0.0000038 (0 hom.)
• Consequence: TP63 NM_001114980.2 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.67
• Publications: 0 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: Orphanet, G2P
• ankyloblepharon-ectodermal defects-cleft lip/palate syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, G2P
• ectrodactyly, ectodermal dysplasia, and cleft lip-palate syndrome 3

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• limb-mammary syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, G2P
• Rapp-Hodgkin syndrome

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• premature ovarian failure 21

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• TP63-related ectodermal dysplasia spectrum with limb and orofacial malformations

  Inheritance: AD Classification: STRONG Submitted by: PanelApp Australia
• 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001114980.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TP63	NM_001114980.2	MANE Plus Clinical	c.-72_-71insAGTG		5_prime_UTR	Exon 1 of 12	NP_001108452.1	Q9H3D4-2
	TP63	NM_003722.5	MANE Select	c.325-18543_325-18542insAGTG		intron	N/A	NP_003713.3
	TP63	NM_001329146.2		c.-72_-71insAGTG		5_prime_UTR	Exon 1 of 11	NP_001316075.1	Q9H3D4-10

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TP63	ENST00000354600.10	TSL:1 MANE Plus Clinical	c.-72_-71insAGTG		5_prime_UTR	Exon 1 of 12	ENSP00000346614.5	Q9H3D4-2
	TP63	ENST00000264731.8	TSL:1 MANE Select	c.325-18543_325-18542insAGTG		intron	N/A	ENSP00000264731.3	Q9H3D4-1
	TP63	ENST00000440651.6	TSL:1	c.325-18543_325-18542insAGTG		intron	N/A	ENSP00000394337.2	Q9H3D4-11

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD4 exome AF: 0.00000375 AC: 5 AN: 1332692 Hom.: 0 Cov.: 32 AF XY: 0.00000304 AC XY: 2 AN XY: 658636

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000349 AC: 1 AN: 28644

American (AMR) AF: 0.00 AC: 0 AN: 29960

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24110

East Asian (EAS) AF: 0.00 AC: 0 AN: 34066

South Asian (SAS) AF: 0.00 AC: 0 AN: 71550

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49848

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5504

European-Non Finnish (NFE) AF: 0.00000387 AC: 4 AN: 1033230

Other (OTH) AF: 0.00 AC: 0 AN: 55780

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000000000000111022), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		5.7

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;