3-189631458-A-T

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.-58A>T variant causes a 5 prime UTR change. The variant allele was found at a frequency of 0.479 in 1,608,672 control chromosomes in the GnomAD database, including 187,736 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.46 (16347 hom., cov: 33)
  • Exomes 𝑓: 0.48 (171389 hom.)
• Consequence: TP63 NM_003722.5 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 4.26

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=-0.55).
• BP6: Variant 3-189631458-A-T is Benign according to our data. Variant chr3-189631458-A-T is described in ClinVar as [Benign]. Clinvar id is 344379.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-189631458-A-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.709 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TP63	NM_003722.5	c.-58A>T		5_prime_UTR_variant	1/14	ENST00000264731.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TP63	ENST00000264731.8	c.-58A>T		5_prime_UTR_variant	1/14	1	NM_003722.5	P4
TP63	ENST00000486398.1	n.43A>T		non_coding_transcript_exon_variant	1/3	3
TP63	ENST00000320472.9			upstream_gene_variant		1
TP63	ENST00000418709.6			upstream_gene_variant		1

Frequencies

GnomAD3 genomes AF: 0.457 AC: 69439 AN: 151898 Hom.: 16344 Cov.: 33

Gnomad AFR AF: 0.399

Gnomad AMI AF: 0.649

Gnomad AMR AF: 0.375

Gnomad ASJ AF: 0.452

Gnomad EAS AF: 0.728

Gnomad SAS AF: 0.490

Gnomad FIN AF: 0.533

Gnomad MID AF: 0.301

Gnomad NFE AF: 0.476

Gnomad OTH AF: 0.424

GnomAD4 exome AF: 0.482 AC: 701754 AN: 1456656 Hom.: 171389 Cov.: 39 AF XY: 0.482 AC XY: 349392 AN XY: 724792

Gnomad4 AFR exome AF: 0.398

Gnomad4 AMR exome AF: 0.336

Gnomad4 ASJ exome AF: 0.448

Gnomad4 EAS exome AF: 0.740

Gnomad4 SAS exome AF: 0.490

Gnomad4 FIN exome AF: 0.524

Gnomad4 NFE exome AF: 0.480

Gnomad4 OTH exome AF: 0.481

GnomAD4 genome AF: 0.457 AC: 69460 AN: 152016 Hom.: 16347 Cov.: 33 AF XY: 0.460 AC XY: 34173 AN XY: 74300

Gnomad4 AFR AF: 0.398

Gnomad4 AMR AF: 0.374

Gnomad4 ASJ AF: 0.452

Gnomad4 EAS AF: 0.728

Gnomad4 SAS AF: 0.490

Gnomad4 FIN AF: 0.533

Gnomad4 NFE AF: 0.476

Gnomad4 OTH AF: 0.421

Alfa AF: 0.313 Hom.: 776

Bravo AF: 0.443

Asia WGS AF: 0.570 AC: 1985 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

TP63-Related Spectrum Disorders Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Orofacial cleft 8 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Ectrodactyly, ectodermal dysplasia, and cleft lip-palate syndrome 3 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
Cadd	Benign	17
Dann	Benign	0.89

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs28673064; hg19: chr3-189349247; COSMIC: COSV53195405; COSMIC: COSV53195405;