Genetic Variant TFAP2E:p.Gly33Glu (chr1-35573997-G-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_178548.4(TFAP2E):c.98G>A(p.Gly33Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000269 in 1,485,608 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G33R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000022 ( 0 hom. )

Consequence

TFAP2E
NM_178548.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.118

Variant links:

Genes affected

TFAP2E (HGNC:30774): (transcription factor AP-2 epsilon) Enables sequence-specific double-stranded DNA binding activity. Predicted to be involved in anatomical structure development; regulation of cell population proliferation; and regulation of transcription by RNA polymerase II. Predicted to act upstream of or within positive regulation of transcription by RNA polymerase II. Predicted to be part of chromatin. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

TFAP2E links:

TFAP2E-AS1 (HGNC:41274): (TFAP2E antisense RNA 1)

TFAP2E-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.15653464).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TFAP2E	NM_178548.4 link	c.98G>A	p.Gly33Glu	missense_variant	Exon 2 of 7	ENST00000373235.4	NP_848643.2	Q6VUC0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TFAP2E	ENST00000373235.4 link	c.98G>A	p.Gly33Glu	missense_variant	Exon 2 of 7	1	NM_178548.4	ENSP00000362332.3	Q6VUC0
TFAP2E-AS1	ENST00000444348.3 link	n.797+363C>T		intron_variant	Intron 2 of 2	3
TFAP2E-AS1	ENST00000425881.1 link	n.-250C>T		upstream_gene_variant		3

Frequencies

GnomAD3 genomes

AF:

0.00000659

AC:

AN:

151856

Hom.:

Cov.:

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:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000225

AC:

AN:

1333752

Hom.:

Cov.:

AF XY:

0.00000304

AC XY:

AN XY:

658470

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000283

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000659

AC:

AN:

151856

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74156

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:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 26, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.98G>A (p.G33E) alteration is located in exon 2 (coding exon 2) of the TFAP2E gene. This alteration results from a G to A substitution at nucleotide position 98, causing the glycine (G) at amino acid position 33 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.45

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.39

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.078

Eigen

Benign

-0.76

Eigen_PC

Benign

-0.77

FATHMM_MKL

Benign

0.27

LIST_S2

Uncertain

0.97

M_CAP

Pathogenic

0.84

MetaRNN

Benign

0.16

MetaSVM

Benign

-0.62

MutationAssessor

Benign

1.1

PrimateAI

Pathogenic

0.94

PROVEAN

Benign

-0.97

REVEL

Benign

0.12

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.020

Polyphen

0.019

Vest4

0.32

MutPred

0.18

Loss of catalytic residue at G33 (P = 0.239);

MVP

0.18

MPC

1.2

ClinPred

0.56

GERP RS

1.6

Varity_R

0.23

gMVP

0.44

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over