chr3-189894547-C-T

Variant names:

• chr3-189894547-C-T
• rs34057105
• NM_003722.5:c.*45C>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.*45C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0673 in 1,605,380 control chromosomes in the GnomAD database, including 4,123 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.053 (291 hom., cov: 32)
  • Exomes 𝑓: 0.069 (3832 hom.)
• Consequence: TP63 NM_003722.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.187

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=-0.83).
• BP6: Variant 3-189894547-C-T is Benign according to our data. Variant chr3-189894547-C-T is described in ClinVar as [Benign]. Clinvar id is 259123.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-189894547-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0775 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TP63	NM_003722.5	c.*45C>T		3_prime_UTR_variant	Exon 14 of 14	ENST00000264731.8	NP_003713.3
TP63	NM_001114980.2	c.*45C>T		3_prime_UTR_variant	Exon 12 of 12	ENST00000354600.10	NP_001108452.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TP63	ENST00000264731.8	c.*45C>T		3_prime_UTR_variant	Exon 14 of 14	1	NM_003722.5	ENSP00000264731.3
TP63	ENST00000354600.10	c.*45C>T		3_prime_UTR_variant	Exon 12 of 12	1	NM_001114980.2	ENSP00000346614.5

Frequencies

GnomAD3 genomes AF: 0.0530 AC: 8054 AN: 152068 Hom.: 291 Cov.: 32

Gnomad AFR AF: 0.0154

Gnomad AMI AF: 0.0769

Gnomad AMR AF: 0.0561

Gnomad ASJ AF: 0.0611

Gnomad EAS AF: 0.000771

Gnomad SAS AF: 0.0222

Gnomad FIN AF: 0.0524

Gnomad MID AF: 0.155

Gnomad NFE AF: 0.0793

Gnomad OTH AF: 0.0811

GnomAD3 exomes AF: 0.0555 AC: 13452 AN: 242320 Hom.: 496 AF XY: 0.0569 AC XY: 7489 AN XY: 131546

Gnomad AFR exome AF: 0.0140

Gnomad AMR exome AF: 0.0402

Gnomad ASJ exome AF: 0.0651

Gnomad EAS exome AF: 0.000166

Gnomad SAS exome AF: 0.0228

Gnomad FIN exome AF: 0.0546

Gnomad NFE exome AF: 0.0829

Gnomad OTH exome AF: 0.0684

GnomAD4 exome AF: 0.0688 AC: 99921 AN: 1453194 Hom.: 3832 Cov.: 30 AF XY: 0.0679 AC XY: 49105 AN XY: 722962

Gnomad4 AFR exome AF: 0.0149

Gnomad4 AMR exome AF: 0.0419

Gnomad4 ASJ exome AF: 0.0639

Gnomad4 EAS exome AF: 0.000228

Gnomad4 SAS exome AF: 0.0244

Gnomad4 FIN exome AF: 0.0565

Gnomad4 NFE exome AF: 0.0781

Gnomad4 OTH exome AF: 0.0653

GnomAD4 genome AF: 0.0529 AC: 8050 AN: 152186 Hom.: 291 Cov.: 32 AF XY: 0.0523 AC XY: 3889 AN XY: 74396

Gnomad4 AFR AF: 0.0154

Gnomad4 AMR AF: 0.0561

Gnomad4 ASJ AF: 0.0611

Gnomad4 EAS AF: 0.000773

Gnomad4 SAS AF: 0.0224

Gnomad4 FIN AF: 0.0524

Gnomad4 NFE AF: 0.0793

Gnomad4 OTH AF: 0.0793

Alfa AF: 0.0659 Hom.: 69

Bravo AF: 0.0528

Asia WGS AF: 0.0180 AC: 64 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

TP63-Related Spectrum Disorders Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

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

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	-0.83
CADD	Benign	3.3
DANN	Benign	0.29

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: rs34057105; hg19: chr3-189612336;