1-35574195-C-T

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

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. 13/22 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
• Publications: 1 publications found

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

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.23223194).
• BS2: High AC in GnomAdExome4 at 8 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_178548.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TFAP2E	NM_178548.4	MANE Select	c.296C>T	p.Ala99Val	missense	Exon 2 of 7	NP_848643.2	Q6VUC0
	TFAP2E-AS1	NR_183383.1		n.880+165G>A		intron	N/A
	TFAP2E-AS1	NR_183385.1		n.777+268G>A		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TFAP2E	ENST00000373235.4	TSL:1 MANE Select	c.296C>T	p.Ala99Val	missense	Exon 2 of 7	ENSP00000362332.3	Q6VUC0
	TFAP2E-AS1	ENST00000444348.4	TSL:3	n.826+165G>A		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00 AC: 0 AN: 24800 AF XY: 0.00

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

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

African (AFR) AF: 0.000280 AC: 6 AN: 21430

American (AMR) AF: 0.00 AC: 0 AN: 11516

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15526

East Asian (EAS) AF: 0.00 AC: 0 AN: 20244

South Asian (SAS) AF: 0.0000162 AC: 1 AN: 61608

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 28510

Middle Eastern (MID) AF: 0.000317 AC: 1 AN: 3152

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 976986

Other (OTH) AF: 0.00 AC: 0 AN: 46264

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		2.8
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
Mutation Taster		=90/10	polymorphism

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

Other links and lift over

dbSNP: rs1258495385; hg19: chr1-36039796;