1-35574195-C-T

Variant names:

• chr1-35574195-C-T
• rs1258495385
• NM_178548.4:c.296C>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_178548.4(TFAP2E):​c.296C>T​(p.Ala99Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000675 in 1,185,236 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. A99T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000067 (0 hom.)
• Consequence: TFAP2E NM_178548.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.85

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

ACMG classification

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=0.23223194).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TFAP2E	NM_178548.4	c.296C>T	p.Ala99Val	missense_variant	Exon 2 of 7	ENST00000373235.4	NP_848643.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TFAP2E	ENST00000373235.4	c.296C>T	p.Ala99Val	missense_variant	Exon 2 of 7	1	NM_178548.4	ENSP00000362332.3
TFAP2E-AS1	ENST00000444348.3	n.797+165G>A		intron_variant	Intron 2 of 2	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000675 AC: 8 AN: 1185236 Hom.: 0 Cov.: 30 AF XY: 0.00000859 AC XY: 5 AN XY: 581870

Gnomad4 AFR exome AF: 0.000280

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000162

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 27, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.296C>T (p.A99V) alteration is located in exon 2 (coding exon 2) of the TFAP2E gene. This alteration results from a C to T substitution at nucleotide position 296, causing the alanine (A) at amino acid position 99 to be replaced by a valine (V). 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	Benign	0.19
BayesDel_addAF	Benign	-0.062	T
BayesDel_noAF	Benign	-0.33
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.17	T
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.46
FATHMM_MKL	Benign	0.39	N
LIST_S2	Benign	0.52	T
M_CAP	Pathogenic	0.78	D
MetaRNN	Benign	0.23	T
MetaSVM	Benign	-0.68	T
MutationAssessor	Benign	1.6	L
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.15
Sift	Benign	0.22	T
Sift4G	Benign	0.49	T
Polyphen		0.18	B
Vest4		0.15
MutPred		0.32		Loss of methylation at R104 (P = 0.123);
MVP		0.54
MPC		0.67
ClinPred		0.44	T
GERP RS		2.9
Varity_R		0.14
gMVP		0.51

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

LitVar

Other links and lift over

dbSNP: rs1258495385; hg19: chr1-36039796;