3-189808465-G-C

Position:

• chr3-189808465-G-C

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP2 PP3_Strong

The NM_003722.5(TP63):​c.518G>C​(p.Gly173Ala) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G173V) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TP63 NM_003722.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 10.0

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PM1: In a DNA_binding_region (size 192) in uniprot entity P63_HUMAN there are 35 pathogenic changes around while only 0 benign (100%) 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 chr3-189808465-G-T is described in Lovd as [Pathogenic].
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), TP63. . Gene score misZ 2.2077 (greater than the threshold 3.09). Trascript score misZ 3.5096 (greater than threshold 3.09). GenCC has associacion of gene with Rapp-Hodgkin syndrome, ADULT syndrome, split hand-foot malformation 4, limb-mammary syndrome, premature ovarian failure 21, split hand-foot malformation, ankyloblepharon-ectodermal defects-cleft lip/palate syndrome, EEC syndrome, ectrodactyly, ectodermal dysplasia, and cleft lip-palate syndrome 3.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.973

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TP63	NM_003722.5	c.518G>C	p.Gly173Ala	missense_variant	4/14	ENST00000264731.8	NP_003713.3
TP63	NM_001114980.2	c.236G>C	p.Gly79Ala	missense_variant	2/12	ENST00000354600.10	NP_001108452.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TP63	ENST00000264731.8	c.518G>C	p.Gly173Ala	missense_variant	4/14	1	NM_003722.5	ENSP00000264731.3
TP63	ENST00000354600.10	c.236G>C	p.Gly79Ala	missense_variant	2/12	1	NM_001114980.2	ENSP00000346614.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.53
CADD	Pathogenic	29
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	0.68	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.95	D
MutationAssessor	Uncertain	2.1	M;M;M;M;M;.;.;.;.;.;.
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-5.7	D;D;D;D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.89
Sift	Uncertain	0.0020	D;D;D;D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.0050	D;D;D;D;D;D;D;D;D;D;D
Polyphen		1.0	D;D;D;D;D;D;.;D;D;.;.
Vest4		0.98
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		0.96
MPC		1.6
ClinPred		0.99	D
GERP RS		5.8
Varity_R		0.96
gMVP		0.84

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-189526254;