3-189625635-A-G

Variant names:

• chr3-189625635-A-G
• rs7610017
• NM_001329964.2:c.56+28397A>G

Variant summary

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

The NM_001329964.2(TP63):​c.56+28397A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.87 in 152,032 control chromosomes in the GnomAD database, including 58,808 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 0.87 (58808 hom., cov: 32)
• Consequence: TP63 NM_001329964.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.26
• Publications: 14 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

ENSG00000306736 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.977 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TP63	NM_001329964.2	c.56+28397A>G		intron_variant	Intron 1 of 13		NP_001316893.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ENSG00000306736	ENST00000820569.1	n.605-1519A>G		intron_variant	Intron 2 of 2
ENSG00000306736	ENST00000820570.1	n.619-1519A>G		intron_variant	Intron 2 of 2

Frequencies

GnomAD3 genomes AF: 0.871 AC: 132264 AN: 151912 Hom.: 58790 Cov.: 32

Gnomad AFR AF: 0.673

Gnomad AMI AF: 0.997

Gnomad AMR AF: 0.928

Gnomad ASJ AF: 0.917

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.960

Gnomad FIN AF: 0.934

Gnomad MID AF: 0.927

Gnomad NFE AF: 0.947

Gnomad OTH AF: 0.892

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

GnomAD4 genome AF: 0.870 AC: 132333 AN: 152032 Hom.: 58808 Cov.: 32 AF XY: 0.874 AC XY: 64978 AN XY: 74320

African (AFR) AF: 0.672 AC: 27819 AN: 41372

American (AMR) AF: 0.928 AC: 14177 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.917 AC: 3181 AN: 3470

East Asian (EAS) AF: 1.00 AC: 5178 AN: 5180

South Asian (SAS) AF: 0.959 AC: 4628 AN: 4826

European-Finnish (FIN) AF: 0.934 AC: 9888 AN: 10582

Middle Eastern (MID) AF: 0.932 AC: 274 AN: 294

European-Non Finnish (NFE) AF: 0.947 AC: 64390 AN: 68006

Other (OTH) AF: 0.894 AC: 1889 AN: 2114

Alfa AF: 0.928 Hom.: 212804

Bravo AF: 0.864

Asia WGS AF: 0.964 AC: 3350 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	17
DANN	Benign	0.90
PhyloP100		1.3

Splicing

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

Other links and lift over

dbSNP: rs7610017; hg19: chr3-189343424;