3-189808318-T-A

Variant names:

• chr3-189808318-T-A
• rs1553845417
• NM_003722.5:c.371T>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP2

The NM_003722.5(TP63):​c.371T>A​(p.Ile124Asn) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. I124T) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TP63 NM_003722.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.88
• Publications: 0 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: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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 EEC syndrome, split hand-foot malformation, Rapp-Hodgkin syndrome, ADULT syndrome, limb-mammary syndrome, ankyloblepharon-ectodermal defects-cleft lip/palate syndrome, ectrodactyly, ectodermal dysplasia, and cleft lip-palate syndrome 3, split hand-foot malformation 4, premature ovarian failure 21, TP63-related ectodermal dysplasia spectrum with limb and orofacial malformations.

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.371T>A	p.Ile124Asn	missense	Exon 4 of 14	NP_003713.3
	TP63	NM_001114980.2	MANE Plus Clinical	c.89T>A	p.Ile30Asn	missense	Exon 2 of 12	NP_001108452.1	Q9H3D4-2
	TP63	NM_001329964.2		c.365T>A	p.Ile122Asn	missense	Exon 4 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.371T>A	p.Ile124Asn	missense	Exon 4 of 14	ENSP00000264731.3	Q9H3D4-1
	TP63	ENST00000354600.10	TSL:1 MANE Plus Clinical	c.89T>A	p.Ile30Asn	missense	Exon 2 of 12	ENSP00000346614.5	Q9H3D4-2
	TP63	ENST00000440651.6	TSL:1	c.371T>A	p.Ile124Asn	missense	Exon 4 of 14	ENSP00000394337.2	Q9H3D4-11

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.40	T
Eigen	Uncertain	0.24
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.32	D
MetaRNN	Uncertain	0.58	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.3	L
PhyloP100		6.9
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-0.80	N
REVEL	Uncertain	0.58
Sift	Benign	0.29	T
Sift4G	Benign	0.33	T
Polyphen		0.030	B
Vest4		0.86
MutPred		0.29		Loss of helix (P = 0.0237)
MVP		0.98
MPC		1.6
ClinPred		0.88	D
GERP RS		5.8
Varity_R		0.25
gMVP		0.57
Mutation Taster		=47/53	disease causing

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: rs1553845417; hg19: chr3-189526107;