rs6789961

chr3-189869302-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003722.5(TP63):c.1130-22A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.234 in 1,607,668 control chromosomes in the GnomAD database, including 50,107 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.32 (9766 hom., cov: 32)
  • Exomes 𝑓: 0.23 (40341 hom.)
• Consequence: TP63 NM_003722.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.14

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BP6: Variant 3-189869302-A-G is Benign according to our data. Variant chr3-189869302-A-G is described in ClinVar as [Benign]. Clinvar id is 259124.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-189869302-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.577 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TP63	NM_001114980.2	c.848-22A>G		intron_variant		ENST00000354600.10
TP63	NM_003722.5	c.1130-22A>G		intron_variant		ENST00000264731.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TP63	ENST00000264731.8	c.1130-22A>G		intron_variant		1	NM_003722.5	P4
TP63	ENST00000354600.10	c.848-22A>G		intron_variant		1	NM_001114980.2	A1

Frequencies

GnomAD3 genomes AF: 0.316 AC: 48059 AN: 151942 Hom.: 9745 Cov.: 32

Gnomad AFR AF: 0.583

Gnomad AMI AF: 0.224

Gnomad AMR AF: 0.214

Gnomad ASJ AF: 0.262

Gnomad EAS AF: 0.151

Gnomad SAS AF: 0.190

Gnomad FIN AF: 0.214

Gnomad MID AF: 0.446

Gnomad NFE AF: 0.218

Gnomad OTH AF: 0.318

GnomAD3 exomes AF: 0.224 AC: 56225 AN: 250938 Hom.: 7671 AF XY: 0.221 AC XY: 29983 AN XY: 135630

Gnomad AFR exome AF: 0.593

Gnomad AMR exome AF: 0.135

Gnomad ASJ exome AF: 0.265

Gnomad EAS exome AF: 0.156

Gnomad SAS exome AF: 0.185

Gnomad FIN exome AF: 0.210

Gnomad NFE exome AF: 0.219

Gnomad OTH exome AF: 0.232

GnomAD4 exome AF: 0.226 AC: 328802 AN: 1455606 Hom.: 40341 Cov.: 30 AF XY: 0.224 AC XY: 162432 AN XY: 724606

Gnomad4 AFR exome AF: 0.600

Gnomad4 AMR exome AF: 0.146

Gnomad4 ASJ exome AF: 0.269

Gnomad4 EAS exome AF: 0.150

Gnomad4 SAS exome AF: 0.186

Gnomad4 FIN exome AF: 0.207

Gnomad4 NFE exome AF: 0.222

Gnomad4 OTH exome AF: 0.247

GnomAD4 genome AF: 0.316 AC: 48113 AN: 152062 Hom.: 9766 Cov.: 32 AF XY: 0.311 AC XY: 23098 AN XY: 74338

Gnomad4 AFR AF: 0.583

Gnomad4 AMR AF: 0.213

Gnomad4 ASJ AF: 0.262

Gnomad4 EAS AF: 0.151

Gnomad4 SAS AF: 0.191

Gnomad4 FIN AF: 0.214

Gnomad4 NFE AF: 0.218

Gnomad4 OTH AF: 0.313

Alfa AF: 0.241 Hom.: 7483

Bravo AF: 0.330

Asia WGS AF: 0.178 AC: 617 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
Cadd	Benign	14
Dann	Benign	0.61

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.17		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: rs6789961; hg19: chr3-189587091; COSMIC: COSV53195425;