chr6-10404523-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2PP3_StrongPP5_Moderate

The NM_001372066.1(TFAP2A):​c.755G>A​(p.Gly252Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

Frequency

Genomes: not found (cov: 33)

Consequence

TFAP2A
NM_001372066.1 missense

Scores

16
2
1

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 7.51
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]
TFAP2A-AS2 (HGNC:52289): (TFAP2A antisense RNA 2) The product of this intronless gene is a capped lncRNA that is nuclear-enriched and associated with chromatin. The encoded transcript may be involved in the regulation of developmental gene expression in a context-dependent manner, functioning as a repressor in non-pluripotent cells and an activator in pluripotent cells. Transcription of this gene is activated in 8-cell human embryos during the major wave of zygotic genome activation, independently of and prior to the activation of TFAP2A, an overlapping gene found on the opposite strand. Expression of this gene is characterized by high cell-to-cell variability in the cells of totipotent human embryos and in stable cell lines. [provided by RefSeq, Mar 2017]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.988
PP5
Variant 6-10404523-C-T is Pathogenic according to our data. Variant chr6-10404523-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 547800.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
TFAP2ANM_001372066.1 linkc.755G>A p.Gly252Asp missense_variant 4/7 ENST00000379613.10 NP_001358995.1
TFAP2ANM_001042425.3 linkc.737G>A p.Gly246Asp missense_variant 4/7 NP_001035890.1 P05549-6
TFAP2ANM_001032280.3 linkc.731G>A p.Gly244Asp missense_variant 4/7 NP_001027451.1 P05549-5
TFAP2A-AS2NR_145448.1 linkn.22C>T non_coding_transcript_exon_variant 1/1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
TFAP2AENST00000379613.10 linkc.755G>A p.Gly252Asp missense_variant 4/71 NM_001372066.1 ENSP00000368933.5 A0A6E1XE14

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Branchiooculofacial syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingCenter for Human Genetics, Inc, Center for Human Genetics, IncNov 01, 2016- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.58
D
BayesDel_noAF
Pathogenic
0.60
CADD
Pathogenic
34
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.99
.;.;.;D;D;D
Eigen
Pathogenic
0.96
Eigen_PC
Pathogenic
0.90
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
0.99
D;.;D;D;D;.
M_CAP
Pathogenic
0.97
D
MetaRNN
Pathogenic
0.99
D;D;D;D;D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
3.4
.;.;.;M;.;.
PrimateAI
Pathogenic
0.93
D
PROVEAN
Pathogenic
-6.0
D;D;D;D;D;D
REVEL
Pathogenic
0.96
Sift
Pathogenic
0.0
D;D;D;D;D;D
Sift4G
Uncertain
0.0030
D;D;D;D;D;D
Polyphen
1.0, 1.0
.;.;.;D;D;.
Vest4
0.99
MutPred
0.92
.;.;.;Loss of MoRF binding (P = 0.0757);Loss of MoRF binding (P = 0.0757);.;
MVP
0.99
ClinPred
1.0
D
GERP RS
5.5
Varity_R
0.98

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: rs1554111717; hg19: chr6-10404756; API