3-189786702-G-A

Variant names:

• chr3-189786702-G-A
• rs13321831
• NM_003722.5:c.325-21570G>A

Variant summary

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

The NM_003722.5(TP63):​c.325-21570G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0876 in 151,960 control chromosomes in the GnomAD database, including 652 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 0.088 (652 hom., cov: 32)
• Consequence: TP63 NM_003722.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.605
• Publications: 4 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=-0.9).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.121 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.325-21570G>A		intron	N/A	NP_003713.3
	TP63	NM_001329964.2		c.319-21570G>A		intron	N/A	NP_001316893.1
	TP63	NM_001329148.2		c.325-21570G>A		intron	N/A	NP_001316077.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TP63	ENST00000264731.8	TSL:1 MANE Select	c.325-21570G>A		intron	N/A	ENSP00000264731.3
	TP63	ENST00000440651.6	TSL:1	c.325-21570G>A		intron	N/A	ENSP00000394337.2
	TP63	ENST00000392460.7	TSL:1	c.325-21570G>A		intron	N/A	ENSP00000376253.3

Frequencies

GnomAD3 genomes AF: 0.0875 AC: 13288 AN: 151842 Hom.: 650 Cov.: 32

Gnomad AFR AF: 0.123

Gnomad AMI AF: 0.127

Gnomad AMR AF: 0.107

Gnomad ASJ AF: 0.0635

Gnomad EAS AF: 0.0234

Gnomad SAS AF: 0.0286

Gnomad FIN AF: 0.0666

Gnomad MID AF: 0.0605

Gnomad NFE AF: 0.0746

Gnomad OTH AF: 0.0816

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

GnomAD4 genome AF: 0.0876 AC: 13309 AN: 151960 Hom.: 652 Cov.: 32 AF XY: 0.0853 AC XY: 6338 AN XY: 74262

African (AFR) AF: 0.123 AC: 5118 AN: 41450

American (AMR) AF: 0.107 AC: 1637 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.0635 AC: 220 AN: 3466

East Asian (EAS) AF: 0.0234 AC: 121 AN: 5166

South Asian (SAS) AF: 0.0286 AC: 138 AN: 4818

European-Finnish (FIN) AF: 0.0666 AC: 705 AN: 10586

Middle Eastern (MID) AF: 0.0651 AC: 19 AN: 292

European-Non Finnish (NFE) AF: 0.0746 AC: 5064 AN: 67922

Other (OTH) AF: 0.0812 AC: 171 AN: 2106

Alfa AF: 0.0796 Hom.: 1532

Bravo AF: 0.0939

Asia WGS AF: 0.0450 AC: 157 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.41
DANN	Benign	0.72
PhyloP100		-0.60
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs13321831; hg19: chr3-189504491;