1-35574308-C-T

Variant names:

• chr1-35574308-C-T
• rs1649102920
• NM_178548.4:c.409C>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.409C>T​(p.Pro137Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000023 in 1,305,982 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000023 (0 hom.)
• Consequence: TFAP2E NM_178548.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.78

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=0.12510642).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TFAP2E	NM_178548.4	c.409C>T	p.Pro137Ser	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.409C>T	p.Pro137Ser	missense_variant	Exon 2 of 7	1	NM_178548.4	ENSP00000362332.3
TFAP2E-AS1	ENST00000444348.3	n.797+52G>A		intron_variant	Intron 2 of 2	3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000230 AC: 3 AN: 1305982 Hom.: 0 Cov.: 30 AF XY: 0.00000311 AC XY: 2 AN XY: 644118

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000375

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.57e-7

Gnomad4 OTH exome AF: 0.0000186

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 08, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.409C>T (p.P137S) 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 409, causing the proline (P) at amino acid position 137 to be replaced by a serine (S). 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	0.25
BayesDel_addAF	Benign	-0.093	T
BayesDel_noAF	Benign	-0.37
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.039	T
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.12
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.80	T
M_CAP	Pathogenic	0.33	D
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	0.83	L
PrimateAI	Pathogenic	0.95	D
PROVEAN	Benign	-0.88	N
REVEL	Benign	0.17
Sift	Benign	0.71	T
Sift4G	Benign	0.79	T
Polyphen		0.19	B
Vest4		0.15
MutPred		0.21		Loss of glycosylation at T134 (P = 0.0534);
MVP		0.47
MPC		0.81
ClinPred		0.55	D
GERP RS		4.1
Varity_R		0.092
gMVP		0.53

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: rs1649102920; hg19: chr1-36039909;