Genetic Variant NM_003722.5:c.727C>T (chr3-189864379-C-T) – ACMG Classification: Pathogenic (19 pts)

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong

The NM_003722.5(TP63):c.727C>T(p.Arg243Trp) variant causes a missense change. 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. R243Q) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

TP63
NM_003722.5 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:10

Conservation

PhyloP100: 6.17

Publications

22 publications found

Variant links:

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

TP63 links:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 19 ACMG points.

PM1

In a hotspot region, there are 6 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 chr3-189864380-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 6528.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, 0.991

PP5

Variant 3-189864379-C-T is Pathogenic according to our data. Variant chr3-189864379-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 6527.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TP63	NM_003722.5	MANE Select	c.727C>T	p.Arg243Trp	missense	Exon 5 of 14	NP_003713.3
TP63	NM_001114980.2	MANE Plus Clinical	c.445C>T	p.Arg149Trp	missense	Exon 3 of 12	NP_001108452.1	Q9H3D4-2
TP63	NM_001329964.2		c.721C>T	p.Arg241Trp	missense	Exon 5 of 14	NP_001316893.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TP63	ENST00000264731.8	TSL:1 MANE Select	c.727C>T	p.Arg243Trp	missense	Exon 5 of 14	ENSP00000264731.3	Q9H3D4-1
TP63	ENST00000354600.10	TSL:1 MANE Plus Clinical	c.445C>T	p.Arg149Trp	missense	Exon 3 of 12	ENSP00000346614.5	Q9H3D4-2
TP63	ENST00000440651.6	TSL:1	c.727C>T	p.Arg243Trp	missense	Exon 5 of 14	ENSP00000394337.2	Q9H3D4-11

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1461658

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727080

African (AFR)

AF:

0.00

AC:

AN:

33474

American (AMR)

AF:

0.00

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26116

East Asian (EAS)

AF:

0.00

AC:

AN:

39694

South Asian (SAS)

AF:

0.00

AC:

AN:

86230

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111858

Other (OTH)

AF:

0.00

AC:

AN:

60388

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (5)

Ectrodactyly, ectodermal dysplasia, and cleft lip-palate syndrome 3 (2)

Ankyloblepharon-ectodermal defects-cleft lip/palate syndrome;C1785148:Rapp-Hodgkin syndrome;C1851878:Orofacial cleft 8;C1854442:Split hand-foot malformation 4;C1858562:Ectrodactyly, ectodermal dysplasia, and cleft lip-palate syndrome 3;C1863204:ADULT syndrome;C1863753:Limb-mammary syndrome;C5830399:Premature ovarian failure 21 (1)

Rapp-Hodgkin syndrome (1)

TP63-Related Spectrum Disorders (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.55

BayesDel_noAF

Pathogenic

0.55

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.99

Eigen

Pathogenic

0.74

Eigen_PC

Pathogenic

0.67

FATHMM_MKL

Uncertain

0.97

LIST_S2

Pathogenic

0.99

M_CAP

Pathogenic

0.60

MetaRNN

Pathogenic

0.99

MetaSVM

Pathogenic

0.90

MutationAssessor

Uncertain

2.8

PhyloP100

6.2

PrimateAI

Pathogenic

0.91

PROVEAN

Pathogenic

-7.9

REVEL

Pathogenic

0.95

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.95

MutPred

0.97

Loss of disorder (P = 0.0114)

MVP

0.98

MPC

1.5

ClinPred

1.0

GERP RS

5.0

Varity_R

0.97

gMVP

0.94

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over