3-189631568-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_003722.5(TP63):c.53A>G(p.Tyr18Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,640 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TP63 NM_003722.5 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 2.68

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, TP63
• BP4: Computational evidence support a benign effect (MetaRNN=0.17334908).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TP63	NM_003722.5	c.53A>G	p.Tyr18Cys	missense_variant	1/14	ENST00000264731.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TP63	ENST00000264731.8	c.53A>G	p.Tyr18Cys	missense_variant	1/14	1	NM_003722.5	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460640 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 726686

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

Premature ovarian insufficiency Uncertain:1

Uncertain significance, no assertion criteria provided

research

Reproductive Development, Murdoch Childrens Research Institute

Mar 01, 2022

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
Cadd	Benign	23
Dann	Uncertain	0.99
DEOGEN2	Benign	0.35	T;.;.;.;.
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.011
FATHMM_MKL	Benign	0.63	D
LIST_S2	Benign	0.85	T;T;T;T;T
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.17	T;T;T;T;T
MetaSVM	Pathogenic	0.90	D
MutationAssessor	Benign	0.0	N;N;N;N;N
MutationTaster	Benign	0.74	D;D;D;D;D;N
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-0.24	N;N;N;N;N
REVEL	Uncertain	0.44
Sift	Uncertain	0.0040	D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D
Polyphen		0.0	B;B;B;B;.
Vest4		0.25
MutPred		0.40		Gain of glycosylation at Y18 (P = 0.0275);Gain of glycosylation at Y18 (P = 0.0275);Gain of glycosylation at Y18 (P = 0.0275);Gain of glycosylation at Y18 (P = 0.0275);Gain of glycosylation at Y18 (P = 0.0275);
MVP		0.65
MPC		0.69
ClinPred		0.43	T
GERP RS		4.5
Varity_R		0.089
gMVP		0.28

Splicing

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: chr3-189349357;