rs34875865

chr3-189737892-T-C

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.191+24T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0496 in 1,613,296 control chromosomes in the GnomAD database, including 2,544 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.035 (197 hom., cov: 32)
  • Exomes 𝑓: 0.051 (2347 hom.)
• Consequence: TP63 NM_003722.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.761

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=-0.84).
• BP6: Variant 3-189737892-T-C is Benign according to our data. Variant chr3-189737892-T-C is described in ClinVar as [Benign]. Clinvar id is 259131.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-189737892-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.058 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TP63	NM_003722.5	c.191+24T>C		intron_variant		ENST00000264731.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TP63	ENST00000264731.8	c.191+24T>C		intron_variant		1	NM_003722.5	P4

Frequencies

GnomAD3 genomes AF: 0.0354 AC: 5391 AN: 152100 Hom.: 197 Cov.: 32

Gnomad AFR AF: 0.00789

Gnomad AMI AF: 0.0286

Gnomad AMR AF: 0.0156

Gnomad ASJ AF: 0.00490

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0168

Gnomad FIN AF: 0.0557

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0595

Gnomad OTH AF: 0.0287

GnomAD3 exomes AF: 0.0379 AC: 9475 AN: 250330 Hom.: 312 AF XY: 0.0377 AC XY: 5096 AN XY: 135322

Gnomad AFR exome AF: 0.00727

Gnomad AMR exome AF: 0.0162

Gnomad ASJ exome AF: 0.00358

Gnomad EAS exome AF: 0.0000546

Gnomad SAS exome AF: 0.0141

Gnomad FIN exome AF: 0.0553

Gnomad NFE exome AF: 0.0611

Gnomad OTH exome AF: 0.0385

GnomAD4 exome AF: 0.0510 AC: 74549 AN: 1461078 Hom.: 2347 Cov.: 31 AF XY: 0.0501 AC XY: 36421 AN XY: 726834

Gnomad4 AFR exome AF: 0.00774

Gnomad4 AMR exome AF: 0.0167

Gnomad4 ASJ exome AF: 0.00452

Gnomad4 EAS exome AF: 0.0000505

Gnomad4 SAS exome AF: 0.0152

Gnomad4 FIN exome AF: 0.0571

Gnomad4 NFE exome AF: 0.0598

Gnomad4 OTH exome AF: 0.0401

GnomAD4 genome AF: 0.0354 AC: 5392 AN: 152218 Hom.: 197 Cov.: 32 AF XY: 0.0339 AC XY: 2526 AN XY: 74436

Gnomad4 AFR AF: 0.00787

Gnomad4 AMR AF: 0.0156

Gnomad4 ASJ AF: 0.00490

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0172

Gnomad4 FIN AF: 0.0557

Gnomad4 NFE AF: 0.0595

Gnomad4 OTH AF: 0.0284

Alfa AF: 0.0486 Hom.: 86

Bravo AF: 0.0317

Asia WGS AF: 0.00808 AC: 30 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	-0.84
Cadd	Benign	5.9
Dann	Benign	0.73

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs34875865; hg19: chr3-189455681; COSMIC: COSV53198294;