rs80338915

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The NM_003221.4(TFAP2B):​c.854G>A​(p.Arg285Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,882 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 Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

TFAP2B
NM_003221.4 missense

Scores

15
3
1

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3O:1

Conservation

PhyloP100: 10.0
Variant links:
Genes affected
TFAP2B (HGNC:11743): (transcription factor AP-2 beta) This gene encodes a member of the AP-2 family of transcription factors. AP-2 proteins form homo- or hetero-dimers with other AP-2 family members and bind specific DNA sequences. They are thought to stimulate cell proliferation and suppress terminal differentiation of specific cell types during embryonic development. Specific AP-2 family members differ in their expression patterns and binding affinity for different promoters. This protein functions as both a transcriptional activator and repressor. Mutations in this gene result in autosomal dominant Char syndrome, suggesting that this gene functions in the differentiation of neural crest cell derivatives. [provided by RefSeq, Jul 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.992
PP5
Variant 6-50838007-G-A is Pathogenic according to our data. Variant chr6-50838007-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 8043.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TFAP2BNM_003221.4 linkc.854G>A p.Arg285Gln missense_variant Exon 5 of 7 ENST00000393655.4 NP_003212.2 Q92481-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TFAP2BENST00000393655.4 linkc.854G>A p.Arg285Gln missense_variant Exon 5 of 7 1 NM_003221.4 ENSP00000377265.2 Q92481-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461882
Hom.:
0
Cov.:
31
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:
8.99e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:3Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Char syndrome Pathogenic:2Other:1
Sep 08, 2017
Embryology Laboratory, Victor Chang Cardiac Research Institute
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: research

This variant was identified in an Australian family of Caucasian descent. This novel missense mutation (with respect to ExAC) segregates completely with disease in 7 individuals across 3 generations. All carriers of this variant exhibit suble characteristic CHAR syndrome features, except one individual who appears asymptomatic, suggesting incomplete penetrance of this variant. -

Oct 01, 2001
OMIM
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

-
GeneReviews
Significance: not provided
Review Status: no classification provided
Collection Method: literature only

- -

not provided Pathogenic:1
Dec 27, 2022
GeneDx
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Published functional studies suggest a damaging effect; specifically, expression studies indicate R274Q results in reduced transactivation function via decreased DNA binding capacity (Zhao et al., 2001); Not observed in large population cohorts (gnomAD); Known as R274Q by alternate nomenclature; This variant is associated with the following publications: (PMID: 29555671, 11505339, 25500235) -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.57
D
BayesDel_noAF
Pathogenic
0.58
CADD
Pathogenic
34
DANN
Pathogenic
1.0
DEOGEN2
Pathogenic
0.98
D
Eigen
Pathogenic
1.0
Eigen_PC
Pathogenic
0.99
FATHMM_MKL
Uncertain
0.97
D
LIST_S2
Pathogenic
0.99
D
M_CAP
Pathogenic
0.58
D
MetaRNN
Pathogenic
0.99
D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
3.5
M
PrimateAI
Uncertain
0.78
T
PROVEAN
Uncertain
-3.8
D
REVEL
Pathogenic
0.97
Sift
Pathogenic
0.0
D
Sift4G
Pathogenic
0.0
D
Polyphen
1.0
D
Vest4
0.93
MutPred
0.96
Loss of MoRF binding (P = 0.0707);
MVP
1.0
MPC
1.8
ClinPred
1.0
D
GERP RS
5.6
Varity_R
0.80
gMVP
0.82

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: rs80338915; hg19: chr6-50805720; COSMIC: COSV53831861; API