1-35574194-G-T

Variant names:

• chr1-35574194-G-T
• rs1197892587
• NM_178548.4:c.295G>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.295G>T​(p.Ala99Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000003 in 1,332,910 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. 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: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000017 (0 hom.)
• Consequence: TFAP2E NM_178548.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.47

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=0.13261965).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TFAP2E	NM_178548.4	c.295G>T	p.Ala99Ser	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.295G>T	p.Ala99Ser	missense_variant	Exon 2 of 7	1	NM_178548.4	ENSP00000362332.3
TFAP2E-AS1	ENST00000444348.3	n.797+166C>A		intron_variant	Intron 2 of 2	3

Frequencies

GnomAD3 genomes AF: 0.0000134 AC: 2 AN: 148756 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000243

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: 0.0000150

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000169 AC: 2 AN: 1184154 Hom.: 0 Cov.: 30 AF XY: 0.00000172 AC XY: 1 AN XY: 581212

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: 0.00000205

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000134 AC: 2 AN: 148756 Hom.: 0 Cov.: 32 AF XY: 0.0000138 AC XY: 1 AN XY: 72520

Gnomad4 AFR AF: 0.0000243

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: 0.0000150

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	16
DANN	Uncertain	0.98
DEOGEN2	Benign	0.049	T
Eigen	Benign	-0.73
Eigen_PC	Benign	-0.71
FATHMM_MKL	Benign	0.69	D
LIST_S2	Benign	0.41	T
M_CAP	Pathogenic	0.63	D
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	0.67	N
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-0.67	N
REVEL	Benign	0.12
Sift	Benign	0.33	T
Sift4G	Benign	0.43	T
Polyphen		0.0030	B
Vest4		0.12
MutPred		0.28		Loss of helix (P = 0.0093);
MVP		0.42
MPC		0.65
ClinPred		0.059	T
GERP RS		0.51
Varity_R		0.16
gMVP		0.39

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: rs1197892587; hg19: chr1-36039795;