chr3-189879066-A-G

Variant names:

• chr3-189879066-A-G
• rs1515490
• NM_003722.5:c.1349+6071A>G

Variant summary

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

The NM_003722.5(TP63):​c.1349+6071A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.161 in 152,292 control chromosomes in the GnomAD database, including 2,492 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 0.16 (2492 hom., cov: 32)
• Consequence: TP63 NM_003722.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0380
• Publications: 8 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=-0.89).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.224 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.1349+6071A>G		intron	N/A	NP_003713.3
	TP63	NM_001114980.2	MANE Plus Clinical	c.1067+6071A>G		intron	N/A	NP_001108452.1
	TP63	NM_001329964.2		c.1343+6071A>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.1349+6071A>G		intron	N/A	ENSP00000264731.3
	TP63	ENST00000354600.10	TSL:1 MANE Plus Clinical	c.1067+6071A>G		intron	N/A	ENSP00000346614.5
	TP63	ENST00000440651.6	TSL:1	c.1337+6071A>G		intron	N/A	ENSP00000394337.2

Frequencies

GnomAD3 genomes AF: 0.162 AC: 24595 AN: 152174 Hom.: 2494 Cov.: 32

Gnomad AFR AF: 0.0517

Gnomad AMI AF: 0.133

Gnomad AMR AF: 0.200

Gnomad ASJ AF: 0.161

Gnomad EAS AF: 0.172

Gnomad SAS AF: 0.0987

Gnomad FIN AF: 0.138

Gnomad MID AF: 0.193

Gnomad NFE AF: 0.227

Gnomad OTH AF: 0.190

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

GnomAD4 genome AF: 0.161 AC: 24592 AN: 152292 Hom.: 2492 Cov.: 32 AF XY: 0.157 AC XY: 11653 AN XY: 74448

African (AFR) AF: 0.0517 AC: 2150 AN: 41572

American (AMR) AF: 0.199 AC: 3051 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.161 AC: 560 AN: 3468

East Asian (EAS) AF: 0.172 AC: 890 AN: 5188

South Asian (SAS) AF: 0.0992 AC: 478 AN: 4820

European-Finnish (FIN) AF: 0.138 AC: 1468 AN: 10602

Middle Eastern (MID) AF: 0.187 AC: 55 AN: 294

European-Non Finnish (NFE) AF: 0.227 AC: 15418 AN: 68020

Other (OTH) AF: 0.190 AC: 401 AN: 2116

Alfa AF: 0.194 Hom.: 4194

Bravo AF: 0.164

Asia WGS AF: 0.122 AC: 428 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.2
DANN	Benign	0.45
PhyloP100		-0.038
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: rs1515490; hg19: chr3-189596855;