chr3-189631458-A-T

Position:

chr3-189631458-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 4.26

Variant links:

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]

TP63 links:

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ACMG classification

Classification made for transcript

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 linkuse as main transcript	c.-58A>T		5_prime_UTR_variant	1/14	ENST00000264731.8

Ensembl

Gene	Transcript	HGVSc	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TP63	ENST00000264731.8 linkuse as main transcript	c.-58A>T	5_prime_UTR_variant	1/14	1	NM_003722.5	P4	Q9H3D4-1
TP63	ENST00000486398.1 linkuse as main transcript	n.43A>T	non_coding_transcript_exon_variant	1/3	3
TP63	ENST00000320472.9 linkuse as main transcript		upstream_gene_variant		1			Q9H3D4-7
TP63	ENST00000418709.6 linkuse as main transcript		upstream_gene_variant		1			Q9H3D4-5

Frequencies

GnomAD3 genomes

AF:

0.457

AC:

69439

AN:

151898

Hom.:

16344

Cov.:

show subpopulations

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.:

AF XY:

0.482

AC XY:

349392

AN XY:

724792

show subpopulations

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.:

AF XY:

0.460

AC XY:

34173

AN XY:

74300

show subpopulations

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

LINK: link

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

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

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.55

CADD

Benign

DANN

Benign

0.89

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over