rs7619549

Variant names:

• chr3-189804469-A-G
• rs7619549
• NM_003722.5:c.325-3803A>G

Your query was ambiguous. Multiple possible variants found:

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

Variant summary

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

The ENST00000264731.8(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 ENST00000264731.8 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.21
• 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=-0.82).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.526 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000264731.8. 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.325-3803A>G		intron	N/A	NP_003713.3
	TP63	NM_001114980.2	MANE Plus Clinical	c.43-3803A>G		intron	N/A	NP_001108452.1
	TP63	NM_001329964.2		c.319-3803A>G		intron	N/A	NP_001316893.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TP63	ENST00000264731.8	TSL:1 MANE Select	c.325-3803A>G		intron	N/A	ENSP00000264731.3
	TP63	ENST00000354600.10	TSL:1 MANE Plus Clinical	c.43-3803A>G		intron	N/A	ENSP00000346614.5
	TP63	ENST00000440651.6	TSL:1	c.325-3803A>G		intron	N/A	ENSP00000394337.2

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

African (AFR) AF: 0.352 AC: 14583 AN: 41444

American (AMR) AF: 0.435 AC: 6648 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.452 AC: 1566 AN: 3464

East Asian (EAS) AF: 0.175 AC: 906 AN: 5184

South Asian (SAS) AF: 0.366 AC: 1764 AN: 4816

European-Finnish (FIN) AF: 0.389 AC: 4106 AN: 10556

Middle Eastern (MID) AF: 0.479 AC: 140 AN: 292

European-Non Finnish (NFE) AF: 0.531 AC: 36098 AN: 67980

Other (OTH) AF: 0.463 AC: 978 AN: 2114

Alfa AF: 0.500 Hom.: 84455

Bravo AF: 0.443

Asia WGS AF: 0.274 AC: 955 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	6.8
DANN	Benign	0.75
PhyloP100		1.2
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs7619549; hg19: chr3-189522258;