rs7619526

Variant names:

• chr3-189746452-G-A
• rs7619526
• NM_003722.5:c.324+7678G>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.324+7678G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.622 in 151,260 control chromosomes in the GnomAD database, including 29,407 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 0.62 (29407 hom., cov: 30)
• Consequence: TP63 NM_003722.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.926
• 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=-0.91).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.684 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.324+7678G>A		intron	N/A	NP_003713.3
	TP63	NM_001329964.2		c.318+7678G>A		intron	N/A	NP_001316893.1
	TP63	NM_001329148.2		c.324+7678G>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.324+7678G>A		intron	N/A	ENSP00000264731.3
	TP63	ENST00000440651.6	TSL:1	c.324+7678G>A		intron	N/A	ENSP00000394337.2
	TP63	ENST00000392460.7	TSL:1	c.324+7678G>A		intron	N/A	ENSP00000376253.3

Frequencies

GnomAD3 genomes AF: 0.622 AC: 94026 AN: 151142 Hom.: 29366 Cov.: 30

Gnomad AFR AF: 0.690

Gnomad AMI AF: 0.611

Gnomad AMR AF: 0.670

Gnomad ASJ AF: 0.594

Gnomad EAS AF: 0.607

Gnomad SAS AF: 0.626

Gnomad FIN AF: 0.567

Gnomad MID AF: 0.579

Gnomad NFE AF: 0.581

Gnomad OTH AF: 0.614

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

GnomAD4 genome AF: 0.622 AC: 94131 AN: 151260 Hom.: 29407 Cov.: 30 AF XY: 0.623 AC XY: 45977 AN XY: 73844

African (AFR) AF: 0.691 AC: 28485 AN: 41244

American (AMR) AF: 0.671 AC: 10186 AN: 15188

Ashkenazi Jewish (ASJ) AF: 0.594 AC: 2051 AN: 3452

East Asian (EAS) AF: 0.607 AC: 3127 AN: 5154

South Asian (SAS) AF: 0.627 AC: 3011 AN: 4800

European-Finnish (FIN) AF: 0.567 AC: 5891 AN: 10390

Middle Eastern (MID) AF: 0.578 AC: 170 AN: 294

European-Non Finnish (NFE) AF: 0.581 AC: 39378 AN: 67742

Other (OTH) AF: 0.612 AC: 1280 AN: 2092

Alfa AF: 0.592 Hom.: 13575

Bravo AF: 0.630

Asia WGS AF: 0.619 AC: 2150 AN: 3470

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	2.5
DANN	Benign	0.58
PhyloP100		-0.93
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: rs7619526; hg19: chr3-189464241;