rs7619549

Positions:

• chr3-189804469-A-G
• chr3-189804469-A-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_003722.5(TP63):​c.325-3803A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.442 in 152,046 control chromosomes in the GnomAD database, including 15,450 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 0.44 (15450 hom., cov: 32)
• Consequence: TP63 NM_003722.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.21

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.526 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TP63	NM_001114980.2	c.43-3803A>G		intron_variant		ENST00000354600.10	NP_001108452.1
TP63	NM_003722.5	c.325-3803A>G		intron_variant		ENST00000264731.8	NP_003713.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TP63	ENST00000264731.8	c.325-3803A>G		intron_variant		1	NM_003722.5	ENSP00000264731	P4
TP63	ENST00000354600.10	c.43-3803A>G		intron_variant		1	NM_001114980.2	ENSP00000346614	A1

Frequencies

GnomAD3 genomes AF: 0.442 AC: 67165 AN: 151926 Hom.: 15425 Cov.: 32

Gnomad AFR AF: 0.352

Gnomad AMI AF: 0.482

Gnomad AMR AF: 0.435

Gnomad ASJ AF: 0.452

Gnomad EAS AF: 0.174

Gnomad SAS AF: 0.365

Gnomad FIN AF: 0.389

Gnomad MID AF: 0.462

Gnomad NFE AF: 0.531

Gnomad OTH AF: 0.465

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

GnomAD4 genome AF: 0.442 AC: 67228 AN: 152046 Hom.: 15450 Cov.: 32 AF XY: 0.433 AC XY: 32177 AN XY: 74336

Gnomad4 AFR AF: 0.352

Gnomad4 AMR AF: 0.435

Gnomad4 ASJ AF: 0.452

Gnomad4 EAS AF: 0.175

Gnomad4 SAS AF: 0.366

Gnomad4 FIN AF: 0.389

Gnomad4 NFE AF: 0.531

Gnomad4 OTH AF: 0.463

Alfa AF: 0.509 Hom.: 41613

Bravo AF: 0.443

Asia WGS AF: 0.274 AC: 955 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	6.8
DANN	Benign	0.75

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs7619549; hg19: chr3-189522258;