chr3-189631535-G-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBS1BS2

The NM_003722.5(TP63):​c.20G>T​(p.Arg7Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000124 in 1,612,730 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R7W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00013 ( 3 hom. )

Consequence

TP63
NM_003722.5 missense

Scores

3
7
9

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 4.38
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

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.
BP4
Computational evidence support a benign effect (MetaRNN=0.016358942).
BP6
Variant 3-189631535-G-T is Benign according to our data. Variant chr3-189631535-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 1601412.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS1
Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0000591 (9/152160) while in subpopulation SAS AF= 0.00187 (9/4814). AF 95% confidence interval is 0.000975. There are 0 homozygotes in gnomad4. There are 6 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
High AC in GnomAd4 at 9 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
TP63NM_003722.5 linkuse as main transcriptc.20G>T p.Arg7Leu missense_variant 1/14 ENST00000264731.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
TP63ENST00000264731.8 linkuse as main transcriptc.20G>T p.Arg7Leu missense_variant 1/141 NM_003722.5 P4Q9H3D4-1

Frequencies

GnomAD3 genomes
AF:
0.0000592
AC:
9
AN:
152042
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00187
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000295
AC:
74
AN:
251174
Hom.:
3
AF XY:
0.000368
AC XY:
50
AN XY:
135744
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00235
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000176
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000131
AC:
191
AN:
1460570
Hom.:
3
Cov.:
33
AF XY:
0.000171
AC XY:
124
AN XY:
726646
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00192
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000153
Gnomad4 OTH exome
AF:
0.000133
GnomAD4 genome
AF:
0.0000591
AC:
9
AN:
152160
Hom.:
0
Cov.:
33
AF XY:
0.0000807
AC XY:
6
AN XY:
74372
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00187
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000483
Hom.:
0
Bravo
AF:
0.00000756
TwinsUK
AF:
0.00
AC:
0
ALSPAC
AF:
0.000259
AC:
1
ExAC
AF:
0.000371
AC:
45

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

TP63-Related Spectrum Disorders Benign:1
Benign, criteria provided, single submitterclinical testingInvitaeDec 06, 2022- -
Ankyloblepharon-ectodermal defects-cleft lip/palate syndrome;C1785148:Rapp-Hodgkin ectodermal dysplasia 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 Benign:1
Likely benign, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsDec 02, 2021- -
TP63-related disorder Benign:1
Likely benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesJan 06, 2022This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.12
BayesDel_addAF
Benign
-0.12
T
BayesDel_noAF
Uncertain
0.040
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Benign
0.35
T;.;.;.;.
Eigen
Benign
-0.094
Eigen_PC
Benign
0.15
FATHMM_MKL
Uncertain
0.79
D
LIST_S2
Uncertain
0.90
D;D;D;D;D
M_CAP
Uncertain
0.20
D
MetaRNN
Benign
0.016
T;T;T;T;T
MetaSVM
Pathogenic
0.98
D
MutationAssessor
Benign
0.0
N;N;N;N;N
MutationTaster
Benign
0.97
D;D;D;D;D;N
PrimateAI
Uncertain
0.58
T
PROVEAN
Benign
-0.43
N;N;N;N;N
REVEL
Uncertain
0.47
Sift
Pathogenic
0.0
D;D;D;D;D
Sift4G
Pathogenic
0.0
D;D;D;D;D
Polyphen
0.011
B;B;B;B;.
Vest4
0.50
MutPred
0.40
Loss of glycosylation at S6 (P = 0.0253);Loss of glycosylation at S6 (P = 0.0253);Loss of glycosylation at S6 (P = 0.0253);Loss of glycosylation at S6 (P = 0.0253);Loss of glycosylation at S6 (P = 0.0253);
MVP
0.81
MPC
0.69
ClinPred
0.21
T
GERP RS
4.8
Varity_R
0.24
gMVP
0.53

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs568702479; hg19: chr3-189349324; COSMIC: COSV105867208; API