6-10398544-G-A

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

Scores

12
6
1

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 10.0
Variant links:
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]

Genome browser will be placed here

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
TFAP2ANM_001372066.1 linkc.1193C>T p.Thr398Met missense_variant 7/7 ENST00000379613.10 NP_001358995.1
TFAP2ANM_001042425.3 linkc.1175C>T p.Thr392Met missense_variant 7/7 NP_001035890.1 P05549-6
TFAP2ANM_001032280.3 linkc.1169C>T p.Thr390Met missense_variant 7/7 NP_001027451.1 P05549-5

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
TFAP2AENST00000379613.10 linkc.1193C>T p.Thr398Met missense_variant 7/71 NM_001372066.1 ENSP00000368933.5 A0A6E1XE14

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152224
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
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:
0.00316
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000398
AC:
1
AN:
251406
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135896
show subpopulations
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 SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.00000616
AC:
9
AN:
1461890
Hom.:
0
Cov.:
37
AF XY:
0.00
AC XY:
0
AN XY:
727246
show subpopulations
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:
0.00000180
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000656
AC:
1
AN:
152342
Hom.:
0
Cov.:
33
AF XY:
0.00
AC XY:
0
AN XY:
74494
show subpopulations
Gnomad4 AFR
AF:
0.00
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:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000508
Hom.:
0

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 submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpMay 29, 2022In 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 submitterclinical testingGeneDxFeb 15, 2024Not 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 submitterclinical testingAmbry GeneticsDec 09, 2024The 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 submitterclinical testingFulgent Genetics, Fulgent GeneticsMar 31, 2024- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.48
BayesDel_addAF
Pathogenic
0.44
D
BayesDel_noAF
Pathogenic
0.39
CADD
Pathogenic
32
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.98
.;.;.;D
Eigen
Pathogenic
0.97
Eigen_PC
Pathogenic
0.92
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Uncertain
0.92
D;.;D;D
M_CAP
Pathogenic
0.75
D
MetaRNN
Pathogenic
0.90
D;D;D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Uncertain
2.9
.;.;.;M
PrimateAI
Pathogenic
0.81
D
PROVEAN
Pathogenic
-4.4
D;D;D;D
REVEL
Pathogenic
0.85
Sift
Uncertain
0.0010
D;D;D;D
Sift4G
Uncertain
0.0040
D;D;D;D
Polyphen
1.0
.;.;.;D
Vest4
0.77
MutPred
0.67
.;.;.;Gain of stability (P = 0.0061);
MVP
0.97
ClinPred
1.0
D
GERP RS
5.2
Varity_R
0.55

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1367388357; hg19: chr6-10398777; COSMIC: COSV60232708; COSMIC: COSV60232708; API