rs33979049

Variant names:

• chr3-189866774-C-T
• rs33979049
• NM_003722.5:c.859C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_003722.5(TP63):​c.859C>T​(p.Leu287Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0197 in 1,613,978 control chromosomes in the GnomAD database, including 370 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.014 (23 hom., cov: 32)
  • Exomes 𝑓: 0.020 (347 hom.)
• Consequence: TP63 NM_003722.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.983
• Publications: 12 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.34).
• BP6: Variant 3-189866774-C-T is Benign according to our data. Variant chr3-189866774-C-T is described in ClinVar as Benign. ClinVar VariationId is 259134.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.983 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0143 (2179/152222) while in subpopulation SAS AF = 0.0276 (133/4818). AF 95% confidence interval is 0.0238. There are 23 homozygotes in GnomAd4. There are 1036 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 2179 AD gene.

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.859C>T	p.Leu287Leu	synonymous	Exon 6 of 14	NP_003713.3
	TP63	NM_001114980.2	MANE Plus Clinical	c.577C>T	p.Leu193Leu	synonymous	Exon 4 of 12	NP_001108452.1	Q9H3D4-2
	TP63	NM_001329964.2		c.853C>T	p.Leu285Leu	synonymous	Exon 6 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.859C>T	p.Leu287Leu	synonymous	Exon 6 of 14	ENSP00000264731.3	Q9H3D4-1
	TP63	ENST00000354600.10	TSL:1 MANE Plus Clinical	c.577C>T	p.Leu193Leu	synonymous	Exon 4 of 12	ENSP00000346614.5	Q9H3D4-2
	TP63	ENST00000440651.6	TSL:1	c.859C>T	p.Leu287Leu	synonymous	Exon 6 of 14	ENSP00000394337.2	Q9H3D4-11

Frequencies

GnomAD3 genomes AF: 0.0143 AC: 2181 AN: 152104 Hom.: 23 Cov.: 32

Gnomad AFR AF: 0.00304

Gnomad AMI AF: 0.0868

Gnomad AMR AF: 0.00701

Gnomad ASJ AF: 0.00461

Gnomad EAS AF: 0.0168

Gnomad SAS AF: 0.0278

Gnomad FIN AF: 0.0125

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0215

Gnomad OTH AF: 0.0177

GnomAD2 exomes AF: 0.0163 AC: 4093 AN: 251342 AF XY: 0.0173

Gnomad AFR exome AF: 0.00289

Gnomad AMR exome AF: 0.00648

Gnomad ASJ exome AF: 0.00526

Gnomad EAS exome AF: 0.0120

Gnomad FIN exome AF: 0.0141

Gnomad NFE exome AF: 0.0200

Gnomad OTH exome AF: 0.0132

GnomAD4 exome AF: 0.0202 AC: 29556 AN: 1461756 Hom.: 347 Cov.: 31 AF XY: 0.0205 AC XY: 14924 AN XY: 727170

African (AFR) AF: 0.00245 AC: 82 AN: 33472

American (AMR) AF: 0.00689 AC: 308 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00536 AC: 140 AN: 26132

East Asian (EAS) AF: 0.0227 AC: 901 AN: 39686

South Asian (SAS) AF: 0.0267 AC: 2304 AN: 86250

European-Finnish (FIN) AF: 0.0143 AC: 764 AN: 53418

Middle Eastern (MID) AF: 0.00347 AC: 20 AN: 5768

European-Non Finnish (NFE) AF: 0.0215 AC: 23948 AN: 1111918

Other (OTH) AF: 0.0180 AC: 1089 AN: 60390

GnomAD4 genome AF: 0.0143 AC: 2179 AN: 152222 Hom.: 23 Cov.: 32 AF XY: 0.0139 AC XY: 1036 AN XY: 74418

African (AFR) AF: 0.00303 AC: 126 AN: 41546

American (AMR) AF: 0.00700 AC: 107 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00461 AC: 16 AN: 3472

East Asian (EAS) AF: 0.0168 AC: 87 AN: 5170

South Asian (SAS) AF: 0.0276 AC: 133 AN: 4818

European-Finnish (FIN) AF: 0.0125 AC: 133 AN: 10598

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0215 AC: 1462 AN: 68008

Other (OTH) AF: 0.0170 AC: 36 AN: 2114

Alfa AF: 0.0180 Hom.: 32

Bravo AF: 0.0131

Asia WGS AF: 0.0180 AC: 64 AN: 3478

EpiCase AF: 0.0198

EpiControl AF: 0.0205

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.34
CADD	Benign	7.5
DANN	Benign	0.78
PhyloP100		0.98
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: rs33979049; hg19: chr3-189584563; COSMIC: COSV53206055; COSMIC: COSV53206055;