rs35592567

Variant names:

• chr3-189896847-C-T
• rs35592567
• NM_003722.5:c.*2345C>T

Your query was ambiguous. Multiple possible variants found:

• chr3-189896847-C-T
• chr3-189896847-C-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003722.5(TP63):​c.*2345C>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 0.204 in 213,336 control chromosomes in the GnomAD database, including 4,473 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.21 (3214 hom., cov: 32)
  • Exomes 𝑓: 0.20 (1259 hom.)
• Consequence: TP63 NM_003722.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.617
• Publications: 18 publications found

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 Gene-Disease associations (from GenCC):

• ADULT syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, G2P
• ankyloblepharon-ectodermal defects-cleft lip/palate syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, G2P
• ectrodactyly, ectodermal dysplasia, and cleft lip-palate syndrome 3

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• limb-mammary syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, G2P
• Rapp-Hodgkin syndrome

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• premature ovarian failure 21

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• TP63-related ectodermal dysplasia spectrum with limb and orofacial malformations

  Inheritance: AD Classification: STRONG Submitted by: PanelApp Australia
• split hand-foot malformation 4

  Inheritance: AD Classification: MODERATE Submitted by: Illumina
• EEC syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• split hand-foot malformation

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 3-189896847-C-T is Benign according to our data. Variant chr3-189896847-C-T is described in ClinVar as Benign. ClinVar VariationId is 344431.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.208 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003722.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TP63	NM_003722.5	MANE Select	c.*2345C>T		3_prime_UTR	Exon 14 of 14	NP_003713.3
	TP63	NM_001114980.2	MANE Plus Clinical	c.*2345C>T		3_prime_UTR	Exon 12 of 12	NP_001108452.1	Q9H3D4-2
	TP63	NM_001329964.2		c.*2345C>T		3_prime_UTR	Exon 14 of 14	NP_001316893.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TP63	ENST00000264731.8	TSL:1 MANE Select	c.*2345C>T		3_prime_UTR	Exon 14 of 14	ENSP00000264731.3	Q9H3D4-1
	TP63	ENST00000354600.10	TSL:1 MANE Plus Clinical	c.*2345C>T		3_prime_UTR	Exon 12 of 12	ENSP00000346614.5	Q9H3D4-2

Frequencies

GnomAD3 genomes AF: 0.206 AC: 31242 AN: 151968 Hom.: 3215 Cov.: 32

Gnomad AFR AF: 0.206

Gnomad AMI AF: 0.245

Gnomad AMR AF: 0.162

Gnomad ASJ AF: 0.173

Gnomad EAS AF: 0.166

Gnomad SAS AF: 0.219

Gnomad FIN AF: 0.258

Gnomad MID AF: 0.278

Gnomad NFE AF: 0.210

Gnomad OTH AF: 0.211

GnomAD4 exome AF: 0.201 AC: 12289 AN: 61250 Hom.: 1259 Cov.: 0 AF XY: 0.203 AC XY: 5797 AN XY: 28572

African (AFR) AF: 0.207 AC: 568 AN: 2738

American (AMR) AF: 0.153 AC: 278 AN: 1822

Ashkenazi Jewish (ASJ) AF: 0.184 AC: 711 AN: 3874

East Asian (EAS) AF: 0.155 AC: 1384 AN: 8950

South Asian (SAS) AF: 0.225 AC: 118 AN: 524

European-Finnish (FIN) AF: 0.252 AC: 116 AN: 460

Middle Eastern (MID) AF: 0.240 AC: 94 AN: 392

European-Non Finnish (NFE) AF: 0.212 AC: 7926 AN: 37402

Other (OTH) AF: 0.215 AC: 1094 AN: 5088

GnomAD4 genome AF: 0.205 AC: 31238 AN: 152086 Hom.: 3214 Cov.: 32 AF XY: 0.206 AC XY: 15311 AN XY: 74332

African (AFR) AF: 0.206 AC: 8531 AN: 41488

American (AMR) AF: 0.162 AC: 2478 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.173 AC: 598 AN: 3466

East Asian (EAS) AF: 0.166 AC: 855 AN: 5160

South Asian (SAS) AF: 0.219 AC: 1060 AN: 4830

European-Finnish (FIN) AF: 0.258 AC: 2726 AN: 10548

Middle Eastern (MID) AF: 0.269 AC: 79 AN: 294

European-Non Finnish (NFE) AF: 0.210 AC: 14247 AN: 67994

Other (OTH) AF: 0.208 AC: 441 AN: 2116

Alfa AF: 0.207 Hom.: 711

Bravo AF: 0.198

Asia WGS AF: 0.174 AC: 602 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Ectrodactyly, ectodermal dysplasia, and cleft lip-palate syndrome 3 (1)
-	-	1	Orofacial cleft 8 (1)
-	-	1	TP63-Related Spectrum Disorders (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	9.2
DANN	Benign	0.51
PhyloP100		0.62
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs35592567; hg19: chr3-189614636; COSMIC: COSV53216247; COSMIC: COSV53216247;