rs4686529

Variant names:

• chr3-189779827-A-G
• rs4686529
• NM_003722.5:c.325-28445A>G

Your query was ambiguous. Multiple possible variants found:

• chr3-189779827-A-G
• chr3-189779827-A-T

Variant summary

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

The NM_003722.5(TP63):​c.325-28445A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.465 in 151,948 control chromosomes in the GnomAD database, including 16,769 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 0.46 (16769 hom., cov: 32)
• Consequence: TP63 NM_003722.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.98
• Publications: 6 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.562 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TP63	NM_003722.5	MANE Select	c.325-28445A>G		intron	N/A	NP_003713.3
	TP63	NM_001329964.2		c.319-28445A>G		intron	N/A	NP_001316893.1
	TP63	NM_001329148.2		c.325-28445A>G		intron	N/A	NP_001316077.1	A0A0S2Z4N6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TP63	ENST00000264731.8	TSL:1 MANE Select	c.325-28445A>G		intron	N/A	ENSP00000264731.3	Q9H3D4-1
	TP63	ENST00000440651.6	TSL:1	c.325-28445A>G		intron	N/A	ENSP00000394337.2	Q9H3D4-11
	TP63	ENST00000392460.7	TSL:1	c.325-28445A>G		intron	N/A	ENSP00000376253.3	Q9H3D4-3

Frequencies

GnomAD3 genomes AF: 0.465 AC: 70537 AN: 151830 Hom.: 16744 Cov.: 32

Gnomad AFR AF: 0.509

Gnomad AMI AF: 0.371

Gnomad AMR AF: 0.572

Gnomad ASJ AF: 0.515

Gnomad EAS AF: 0.315

Gnomad SAS AF: 0.298

Gnomad FIN AF: 0.353

Gnomad MID AF: 0.484

Gnomad NFE AF: 0.452

Gnomad OTH AF: 0.488

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

GnomAD4 genome AF: 0.465 AC: 70622 AN: 151948 Hom.: 16769 Cov.: 32 AF XY: 0.458 AC XY: 34027 AN XY: 74268

African (AFR) AF: 0.509 AC: 21083 AN: 41422

American (AMR) AF: 0.572 AC: 8735 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.515 AC: 1787 AN: 3468

East Asian (EAS) AF: 0.315 AC: 1616 AN: 5138

South Asian (SAS) AF: 0.299 AC: 1440 AN: 4822

European-Finnish (FIN) AF: 0.353 AC: 3728 AN: 10556

Middle Eastern (MID) AF: 0.486 AC: 142 AN: 292

European-Non Finnish (NFE) AF: 0.452 AC: 30727 AN: 67970

Other (OTH) AF: 0.488 AC: 1026 AN: 2104

Alfa AF: 0.453 Hom.: 8401

Bravo AF: 0.487

Asia WGS AF: 0.337 AC: 1171 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	9.4
DANN	Benign	0.77
PhyloP100		2.0
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: rs4686529; hg19: chr3-189497616;