chr3-189864452-T-G

Variant names:

• chr3-189864452-T-G
• rs17514215
• NM_003722.5:c.766+34T>G

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+34T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.15 in 1,586,136 control chromosomes in the GnomAD database, including 20,003 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (1397 hom., cov: 31)
  • Exomes 𝑓: 0.15 (18606 hom.)
• Consequence: TP63 NM_003722.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.385
• Publications: 3 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=-0.85).
• BP6: Variant 3-189864452-T-G is Benign according to our data. Variant chr3-189864452-T-G is described in ClinVar as Benign. ClinVar VariationId is 259132.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.171 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+34T>G		intron	N/A	NP_003713.3
	TP63	NM_001114980.2	MANE Plus Clinical	c.484+34T>G		intron	N/A	NP_001108452.1
	TP63	NM_001329964.2		c.760+34T>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.766+34T>G		intron	N/A	ENSP00000264731.3
	TP63	ENST00000354600.10	TSL:1 MANE Plus Clinical	c.484+34T>G		intron	N/A	ENSP00000346614.5
	TP63	ENST00000440651.6	TSL:1	c.766+34T>G		intron	N/A	ENSP00000394337.2

Frequencies

GnomAD3 genomes AF: 0.116 AC: 17506 AN: 151156 Hom.: 1397 Cov.: 31

Gnomad AFR AF: 0.0312

Gnomad AMI AF: 0.121

Gnomad AMR AF: 0.132

Gnomad ASJ AF: 0.174

Gnomad EAS AF: 0.000782

Gnomad SAS AF: 0.0391

Gnomad FIN AF: 0.117

Gnomad MID AF: 0.139

Gnomad NFE AF: 0.174

Gnomad OTH AF: 0.134

GnomAD2 exomes AF: 0.120 AC: 27650 AN: 230566 AF XY: 0.121

Gnomad AFR exome AF: 0.0285

Gnomad AMR exome AF: 0.101

Gnomad ASJ exome AF: 0.169

Gnomad EAS exome AF: 0.000171

Gnomad FIN exome AF: 0.115

Gnomad NFE exome AF: 0.175

Gnomad OTH exome AF: 0.146

GnomAD4 exome AF: 0.153 AC: 220218 AN: 1434868 Hom.: 18606 Cov.: 32 AF XY: 0.150 AC XY: 107115 AN XY: 711830

African (AFR) AF: 0.0262 AC: 859 AN: 32746

American (AMR) AF: 0.103 AC: 4382 AN: 42570

Ashkenazi Jewish (ASJ) AF: 0.167 AC: 4119 AN: 24594

East Asian (EAS) AF: 0.000207 AC: 8 AN: 38572

South Asian (SAS) AF: 0.0449 AC: 3731 AN: 83174

European-Finnish (FIN) AF: 0.123 AC: 6400 AN: 51946

Middle Eastern (MID) AF: 0.118 AC: 647 AN: 5464

European-Non Finnish (NFE) AF: 0.175 AC: 191543 AN: 1096850

Other (OTH) AF: 0.145 AC: 8529 AN: 58952

GnomAD4 genome AF: 0.116 AC: 17507 AN: 151268 Hom.: 1397 Cov.: 31 AF XY: 0.111 AC XY: 8221 AN XY: 73888

African (AFR) AF: 0.0311 AC: 1281 AN: 41210

American (AMR) AF: 0.132 AC: 2008 AN: 15188

Ashkenazi Jewish (ASJ) AF: 0.174 AC: 602 AN: 3456

East Asian (EAS) AF: 0.000783 AC: 4 AN: 5108

South Asian (SAS) AF: 0.0398 AC: 190 AN: 4772

European-Finnish (FIN) AF: 0.117 AC: 1213 AN: 10398

Middle Eastern (MID) AF: 0.143 AC: 42 AN: 294

European-Non Finnish (NFE) AF: 0.174 AC: 11775 AN: 67830

Other (OTH) AF: 0.134 AC: 282 AN: 2104

Alfa AF: 0.135 Hom.: 1071

Bravo AF: 0.113

Asia WGS AF: 0.0210 AC: 74 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	1.6
DANN	Benign	0.66
PhyloP100		-0.39
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: rs17514215; hg19: chr3-189582241; COSMIC: COSV53222444;