rs9332461

Variant names:

• chr3-189624001-G-A
• rs9332461
• ENST00000820571.1:n.1302G>A

Variant summary

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

The ENST00000820571.1(ENSG00000306736):​n.1302G>A variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.34 in 152,000 control chromosomes in the GnomAD database, including 9,156 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 0.34 (9156 hom., cov: 32)
• Consequence: ENSG00000306736 ENST00000820571.1 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.282
• Publications: 9 publications found

Genes affected

ENSG00000306736 (HGNC:):

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=-0.92).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.38 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TP63	NM_001329964.2	c.56+26763G>A		intron_variant	Intron 1 of 13		NP_001316893.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ENSG00000306736	ENST00000820571.1	n.1302G>A		non_coding_transcript_exon_variant	Exon 2 of 2
ENSG00000306736	ENST00000820569.1	n.604+684G>A		intron_variant	Intron 2 of 2
ENSG00000306736	ENST00000820570.1	n.618+684G>A		intron_variant	Intron 2 of 2

Frequencies

GnomAD3 genomes AF: 0.341 AC: 51721 AN: 151882 Hom.: 9152 Cov.: 32

Gnomad AFR AF: 0.284

Gnomad AMI AF: 0.531

Gnomad AMR AF: 0.281

Gnomad ASJ AF: 0.344

Gnomad EAS AF: 0.282

Gnomad SAS AF: 0.293

Gnomad FIN AF: 0.408

Gnomad MID AF: 0.248

Gnomad NFE AF: 0.384

Gnomad OTH AF: 0.315

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

GnomAD4 genome AF: 0.340 AC: 51752 AN: 152000 Hom.: 9156 Cov.: 32 AF XY: 0.339 AC XY: 25147 AN XY: 74288

African (AFR) AF: 0.284 AC: 11770 AN: 41460

American (AMR) AF: 0.281 AC: 4293 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.344 AC: 1194 AN: 3466

East Asian (EAS) AF: 0.282 AC: 1460 AN: 5178

South Asian (SAS) AF: 0.292 AC: 1407 AN: 4816

European-Finnish (FIN) AF: 0.408 AC: 4300 AN: 10544

Middle Eastern (MID) AF: 0.240 AC: 70 AN: 292

European-Non Finnish (NFE) AF: 0.384 AC: 26113 AN: 67956

Other (OTH) AF: 0.314 AC: 663 AN: 2110

Alfa AF: 0.357 Hom.: 1257

Bravo AF: 0.329

Asia WGS AF: 0.290 AC: 1009 AN: 3472

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.49
DANN	Benign	0.52
PhyloP100		-0.28

Splicing

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

Other links and lift over

dbSNP: rs9332461; hg19: chr3-189341790;