6-10398544-G-A
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Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PP3_ModerateBS1_SupportingBS2
The NM_001372066.1(TFAP2A):c.1193C>T(p.Thr398Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000619 in 1,614,232 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000062 ( 0 hom. )
Consequence
TFAP2A
NM_001372066.1 missense
NM_001372066.1 missense
Scores
12
6
1
Clinical Significance
Conservation
PhyloP100: 10.0
Genes affected
TFAP2A (HGNC:11742): (transcription factor AP-2 alpha) The protein encoded by this gene is a transcription factor that binds the consensus sequence 5'-GCCNNNGGC-3'. The encoded protein functions as either a homodimer or as a heterodimer with similar family members. This protein activates the transcription of some genes while inhibiting the transcription of others. Defects in this gene are a cause of branchiooculofacial syndrome (BOFS). Three transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Dec 2009]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -3 ACMG points.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.904
BS1
Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00000616 (9/1461890) while in subpopulation MID AF= 0.00121 (7/5768). AF 95% confidence interval is 0.000569. There are 0 homozygotes in gnomad4_exome. There are 0 alleles in male gnomad4_exome subpopulation. Median coverage is 37. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
BS2
High AC in GnomAdExome4 at 9 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
TFAP2A | NM_001372066.1 | c.1193C>T | p.Thr398Met | missense_variant | 7/7 | ENST00000379613.10 | NP_001358995.1 | |
TFAP2A | NM_001042425.3 | c.1175C>T | p.Thr392Met | missense_variant | 7/7 | NP_001035890.1 | ||
TFAP2A | NM_001032280.3 | c.1169C>T | p.Thr390Met | missense_variant | 7/7 | NP_001027451.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
TFAP2A | ENST00000379613.10 | c.1193C>T | p.Thr398Met | missense_variant | 7/7 | 1 | NM_001372066.1 | ENSP00000368933.5 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152224Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251406Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135896
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GnomAD4 exome AF: 0.00000616 AC: 9AN: 1461890Hom.: 0 Cov.: 37 AF XY: 0.00 AC XY: 0AN XY: 727246
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GnomAD4 genome AF: 0.00000656 AC: 1AN: 152342Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74494
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | May 29, 2022 | In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals affected with TFAP2A-related conditions. This variant is present in population databases (no rsID available, gnomAD no frequency). This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 396 of the TFAP2A protein (p.Thr396Met). - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Feb 15, 2024 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 09, 2024 | The c.1187C>T (p.T396M) alteration is located in exon 7 (coding exon 7) of the TFAP2A gene. This alteration results from a C to T substitution at nucleotide position 1187, causing the threonine (T) at amino acid position 396 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Branchiooculofacial syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Mar 31, 2024 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Pathogenic
.;.;.;D
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;.;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Uncertain
.;.;.;M
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D;D;D;D
REVEL
Pathogenic
Sift
Uncertain
D;D;D;D
Sift4G
Uncertain
D;D;D;D
Polyphen
1.0
.;.;.;D
Vest4
MutPred
0.67
.;.;.;Gain of stability (P = 0.0061);
MVP
ClinPred
D
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Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at