3-189808465-G-T

Variant names:

• chr3-189808465-G-T
• rs113993965
• NM_003722.5:c.518G>T

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Moderate

The NM_003722.5(TP63):​c.518G>T​(p.Gly173Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G173R) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TP63 NM_003722.5 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 10.0
• Publications: 6 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: G2P, Orphanet
• ankyloblepharon-ectodermal defects-cleft lip/palate syndrome

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

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

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

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

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• 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: Pathogenic. The variant received 13 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_003722.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr3-189808464-G-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 383835.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant in the TP63 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 73 curated pathogenic missense variants (we use a threshold of 10). The gene has 15 curated benign missense variants. Gene score misZ: 2.2077 (below the threshold of 3.09). Trascript score misZ: 3.5096 (above the threshold of 3.09). GenCC associations: The gene is linked to Rapp-Hodgkin syndrome, ADULT syndrome, premature ovarian failure 21, limb-mammary syndrome, ectrodactyly, ectodermal dysplasia, and cleft lip-palate syndrome 3, ankyloblepharon-ectodermal defects-cleft lip/palate syndrome, EEC syndrome, split hand-foot malformation, split hand-foot malformation 4.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.977
• PP5: Variant 3-189808465-G-T is Pathogenic according to our data. Variant chr3-189808465-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 430080.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TP63	NM_003722.5	c.518G>T	p.Gly173Val	missense_variant	Exon 4 of 14	ENST00000264731.8	NP_003713.3
TP63	NM_001114980.2	c.236G>T	p.Gly79Val	missense_variant	Exon 2 of 12	ENST00000354600.10	NP_001108452.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TP63	ENST00000264731.8	c.518G>T	p.Gly173Val	missense_variant	Exon 4 of 14	1	NM_003722.5	ENSP00000264731.3
TP63	ENST00000354600.10	c.236G>T	p.Gly79Val	missense_variant	Exon 2 of 12	1	NM_001114980.2	ENSP00000346614.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

May 17, 2017

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The G173V variant in the TP63 gene has been reported previously, sometimes as G134V due to alternate nomenclature, in the heterozygous state, in unrelated individuals with ADULT (acro-dermato-ungual-lacrimal-tooth) syndrome (Prontera et al., 2011; Monti et al., 2013). The G173V variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The G173V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved across species. Transactivation assays in yeast and mammalian cells reveal that the G173V mutant demonstrated a reduction in transactivation ability (Monti et al., 2013). A different missense variant (G173D) has been reported in the Human Gene Mutation Database in association with a TP63-related disorder (Stenson et al., 2014), supporting the functional importance of this region of the protein. We interpret G173V as a pathogenic variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	D;.;.;.;.;.;.;.;.;.;.
Eigen	Pathogenic	0.99
Eigen_PC	Pathogenic	0.96
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.67	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.95	D
MutationAssessor	Uncertain	2.8	M;M;M;M;M;.;.;.;.;.;.
PhyloP100		10
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-8.5	D;D;D;D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	D;D;D;D;D;D;D;D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D;D;D;D;D;D
Polyphen		1.0	D;D;D;D;D;D;.;D;D;.;.
Vest4		0.99
MutPred		0.88		Gain of glycosylation at Y171 (P = 0.006);Gain of glycosylation at Y171 (P = 0.006);Gain of glycosylation at Y171 (P = 0.006);Gain of glycosylation at Y171 (P = 0.006);Gain of glycosylation at Y171 (P = 0.006);.;.;.;.;.;.;
MVP		0.99
MPC		1.7
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.99
gMVP		0.90
Mutation Taster		=0/100	disease causing (ClinVar)

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: rs113993965; hg19: chr3-189526254;