3-189893237-A-G

Variant names:

• chr3-189893237-A-G
• rs4687100
• NM_003722.5:c.1747-969A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_003722.5(TP63):​c.1747-969A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.241 in 152,168 control chromosomes in the GnomAD database, including 4,572 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.24 (4572 hom., cov: 32)
• Consequence: TP63 NM_003722.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.868
• Publications: 8 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.266 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003722.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TP63	NM_003722.5	MANE Select	c.1747-969A>G		intron	N/A	NP_003713.3
	TP63	NM_001114980.2	MANE Plus Clinical	c.1465-969A>G		intron	N/A	NP_001108452.1
	TP63	NM_001329964.2		c.1741-969A>G		intron	N/A	NP_001316893.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TP63	ENST00000264731.8	TSL:1 MANE Select	c.1747-969A>G		intron	N/A	ENSP00000264731.3
	TP63	ENST00000354600.10	TSL:1 MANE Plus Clinical	c.1465-969A>G		intron	N/A	ENSP00000346614.5
	TP63	ENST00000440651.6	TSL:1	c.1735-969A>G		intron	N/A	ENSP00000394337.2

Frequencies

GnomAD3 genomes AF: 0.241 AC: 36699 AN: 152048 Hom.: 4570 Cov.: 32

Gnomad AFR AF: 0.232

Gnomad AMI AF: 0.150

Gnomad AMR AF: 0.248

Gnomad ASJ AF: 0.205

Gnomad EAS AF: 0.181

Gnomad SAS AF: 0.135

Gnomad FIN AF: 0.181

Gnomad MID AF: 0.261

Gnomad NFE AF: 0.270

Gnomad OTH AF: 0.249

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.241 AC: 36724 AN: 152168 Hom.: 4572 Cov.: 32 AF XY: 0.233 AC XY: 17365 AN XY: 74392

African (AFR) AF: 0.232 AC: 9641 AN: 41498

American (AMR) AF: 0.248 AC: 3794 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.205 AC: 710 AN: 3468

East Asian (EAS) AF: 0.182 AC: 940 AN: 5176

South Asian (SAS) AF: 0.135 AC: 651 AN: 4822

European-Finnish (FIN) AF: 0.181 AC: 1917 AN: 10596

Middle Eastern (MID) AF: 0.255 AC: 75 AN: 294

European-Non Finnish (NFE) AF: 0.270 AC: 18336 AN: 67996

Other (OTH) AF: 0.248 AC: 523 AN: 2110

Alfa AF: 0.239 Hom.: 771

Bravo AF: 0.248

Asia WGS AF: 0.148 AC: 520 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	6.9
DANN	Benign	0.69
PhyloP100		0.87
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4687100; hg19: chr3-189611026;