rs2276792

Variant names:

• chr3-189864460-G-A
• rs2276792
• NM_003722.5:c.766+42G>A

Your query was ambiguous. Multiple possible variants found:

• chr3-189864460-G-A
• chr3-189864460-G-C
• chr3-189864460-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003722.5(TP63):​c.766+42G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.116 in 1,577,000 control chromosomes in the GnomAD database, including 14,292 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.19 (3974 hom., cov: 30)
  • Exomes 𝑓: 0.11 (10318 hom.)
• Consequence: TP63 NM_003722.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.36
• Publications: 7 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 3-189864460-G-A is Benign according to our data. Variant chr3-189864460-G-A is described in ClinVar as Benign. ClinVar VariationId is 259133.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.399 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.766+42G>A		intron	N/A	NP_003713.3
	TP63	NM_001114980.2	MANE Plus Clinical	c.484+42G>A		intron	N/A	NP_001108452.1
	TP63	NM_001329964.2		c.760+42G>A		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.766+42G>A		intron	N/A	ENSP00000264731.3
	TP63	ENST00000354600.10	TSL:1 MANE Plus Clinical	c.484+42G>A		intron	N/A	ENSP00000346614.5
	TP63	ENST00000440651.6	TSL:1	c.766+42G>A		intron	N/A	ENSP00000394337.2

Frequencies

GnomAD3 genomes AF: 0.185 AC: 27945 AN: 151040 Hom.: 3967 Cov.: 30

Gnomad AFR AF: 0.404

Gnomad AMI AF: 0.0956

Gnomad AMR AF: 0.110

Gnomad ASJ AF: 0.103

Gnomad EAS AF: 0.152

Gnomad SAS AF: 0.138

Gnomad FIN AF: 0.109

Gnomad MID AF: 0.226

Gnomad NFE AF: 0.0930

Gnomad OTH AF: 0.155

GnomAD2 exomes AF: 0.124 AC: 27684 AN: 223324 AF XY: 0.121

Gnomad AFR exome AF: 0.413

Gnomad AMR exome AF: 0.0676

Gnomad ASJ exome AF: 0.104

Gnomad EAS exome AF: 0.160

Gnomad FIN exome AF: 0.103

Gnomad NFE exome AF: 0.0956

Gnomad OTH exome AF: 0.116

GnomAD4 exome AF: 0.108 AC: 154460 AN: 1425852 Hom.: 10318 Cov.: 31 AF XY: 0.108 AC XY: 76572 AN XY: 706178

African (AFR) AF: 0.417 AC: 13652 AN: 32734

American (AMR) AF: 0.0743 AC: 3085 AN: 41546

Ashkenazi Jewish (ASJ) AF: 0.103 AC: 2480 AN: 24086

East Asian (EAS) AF: 0.161 AC: 6200 AN: 38592

South Asian (SAS) AF: 0.133 AC: 10878 AN: 82074

European-Finnish (FIN) AF: 0.101 AC: 5194 AN: 51380

Middle Eastern (MID) AF: 0.189 AC: 1009 AN: 5342

European-Non Finnish (NFE) AF: 0.0955 AC: 104221 AN: 1091462

Other (OTH) AF: 0.132 AC: 7741 AN: 58636

GnomAD4 genome AF: 0.185 AC: 27963 AN: 151148 Hom.: 3974 Cov.: 30 AF XY: 0.183 AC XY: 13477 AN XY: 73810

African (AFR) AF: 0.404 AC: 16596 AN: 41114

American (AMR) AF: 0.110 AC: 1666 AN: 15180

Ashkenazi Jewish (ASJ) AF: 0.103 AC: 356 AN: 3468

East Asian (EAS) AF: 0.152 AC: 777 AN: 5110

South Asian (SAS) AF: 0.138 AC: 662 AN: 4780

European-Finnish (FIN) AF: 0.109 AC: 1125 AN: 10312

Middle Eastern (MID) AF: 0.216 AC: 63 AN: 292

European-Non Finnish (NFE) AF: 0.0930 AC: 6311 AN: 67888

Other (OTH) AF: 0.153 AC: 320 AN: 2094

Alfa AF: 0.122 Hom.: 1262

Bravo AF: 0.196

Asia WGS AF: 0.145 AC: 505 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.11
DANN	Benign	0.75
PhyloP100		-1.4
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: rs2276792; hg19: chr3-189582249; COSMIC: COSV53216322;