rs9840360

chr3-189873036-G-Achr3-189873036-G-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_003722.5(TP63):c.1349+41G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.206 in 1,613,004 control chromosomes in the GnomAD database, including 36,282 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.25 (5115 hom., cov: 32)
  • Exomes 𝑓: 0.20 (31167 hom.)
• Consequence: TP63 NM_003722.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.66

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 3-189873036-G-A is Benign according to our data. Variant chr3-189873036-G-A is described in ClinVar as [Benign]. Clinvar id is 259126.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-189873036-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.371 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TP63	NM_001114980.2	c.1067+41G>A		intron_variant		ENST00000354600.10
TP63	NM_003722.5	c.1349+41G>A		intron_variant		ENST00000264731.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TP63	ENST00000264731.8	c.1349+41G>A		intron_variant		1	NM_003722.5	P4
TP63	ENST00000354600.10	c.1067+41G>A		intron_variant		1	NM_001114980.2	A1

Frequencies

GnomAD3 genomes AF: 0.246 AC: 37391 AN: 151796 Hom.: 5111 Cov.: 32

Gnomad AFR AF: 0.376

Gnomad AMI AF: 0.246

Gnomad AMR AF: 0.167

Gnomad ASJ AF: 0.163

Gnomad EAS AF: 0.165

Gnomad SAS AF: 0.229

Gnomad FIN AF: 0.250

Gnomad MID AF: 0.291

Gnomad NFE AF: 0.197

Gnomad OTH AF: 0.224

GnomAD3 exomes AF: 0.202 AC: 50518 AN: 250562 Hom.: 5619 AF XY: 0.204 AC XY: 27666 AN XY: 135382

Gnomad AFR exome AF: 0.379

Gnomad AMR exome AF: 0.102

Gnomad ASJ exome AF: 0.159

Gnomad EAS exome AF: 0.178

Gnomad SAS exome AF: 0.221

Gnomad FIN exome AF: 0.242

Gnomad NFE exome AF: 0.201

Gnomad OTH exome AF: 0.202

GnomAD4 exome AF: 0.202 AC: 295645 AN: 1461090 Hom.: 31167 Cov.: 34 AF XY: 0.203 AC XY: 147836 AN XY: 726900

Gnomad4 AFR exome AF: 0.380

Gnomad4 AMR exome AF: 0.112

Gnomad4 ASJ exome AF: 0.166

Gnomad4 EAS exome AF: 0.166

Gnomad4 SAS exome AF: 0.222

Gnomad4 FIN exome AF: 0.249

Gnomad4 NFE exome AF: 0.198

Gnomad4 OTH exome AF: 0.217

GnomAD4 genome AF: 0.246 AC: 37398 AN: 151914 Hom.: 5115 Cov.: 32 AF XY: 0.245 AC XY: 18167 AN XY: 74242

Gnomad4 AFR AF: 0.376

Gnomad4 AMR AF: 0.167

Gnomad4 ASJ AF: 0.163

Gnomad4 EAS AF: 0.165

Gnomad4 SAS AF: 0.229

Gnomad4 FIN AF: 0.250

Gnomad4 NFE AF: 0.197

Gnomad4 OTH AF: 0.221

Alfa AF: 0.208 Hom.: 678

Bravo AF: 0.246

Asia WGS AF: 0.186 AC: 646 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
Cadd	Benign	0.018
Dann	Benign	0.50

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

Publications

LitVar

Other links and lift over

dbSNP: rs9840360; hg19: chr3-189590825; COSMIC: COSV53198302;