6-10404509-T-C

Variant names:

Variant summary

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

The NM_001372066.1(TFAP2A):c.769A>G(p.Arg257Gly) variant causes a missense, splice region 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. 14/24 in silico tools predict a damaging outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

TFAP2A
NM_001372066.1 missense, splice_region

Scores

Splicing: ADA: 0.9999

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10

Conservation

PhyloP100: 7.55

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 links:

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]

TFAP2A-AS2 links:

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

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.

PP5

Variant 6-10404509-T-C is Pathogenic according to our data. Variant chr6-10404509-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 17937.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-10404509-T-C is described in Lovd as [Pathogenic]. Variant chr6-10404509-T-C is described in Lovd as [Likely_pathogenic]. Variant chr6-10404509-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TFAP2A	NM_001372066.1 link	c.769A>G	p.Arg257Gly	missense_variant, splice_region_variant	Exon 4 of 7	ENST00000379613.10	NP_001358995.1
TFAP2A	NM_001042425.3 link	c.751A>G	p.Arg251Gly	missense_variant, splice_region_variant	Exon 4 of 7		NP_001035890.1	P05549-6
TFAP2A	NM_001032280.3 link	c.745A>G	p.Arg249Gly	missense_variant, splice_region_variant	Exon 4 of 7		NP_001027451.1	P05549-5
TFAP2A-AS2	NR_145448.1 link	n.8T>C		non_coding_transcript_exon_variant	Exon 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TFAP2A	ENST00000379613.10 link	c.769A>G	p.Arg257Gly	missense_variant, splice_region_variant	Exon 4 of 7	1	NM_001372066.1	ENSP00000368933.5		A0A6E1XE14

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1443814

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

716896

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Branchiooculofacial syndrome

Pathogenic:7

Apr 01, 2010

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Aug 16, 2023

Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Laboratory of Genetic Epidemiology, Research Centre for Medical Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Jun 17, 2020

Cytogenetics and Genomics Lab, Cyprus Institute Of Neurology and Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Oct 23, 2019

HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

ACMG codes:PS2; PS4M; PM2; PP3 -

Mar 24, 2022

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 01, 2016

Center for Human Genetics, Inc, Center for Human Genetics, Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Pathogenic:3

Oct 17, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine with glycine at codon 255 of the TFAP2A protein (p.Arg255Gly). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and glycine. This variant is not present in population databases (ExAC no frequency). This missense change has been observed in individuals with branchiooculofacial syndrome (PMID: 18423521, 20358615, 20461149, 21539471, 25590586). ClinVar contains an entry for this variant (Variation ID: 17937). 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: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change affects TFAP2A function (PMID: 23578821). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Mar 01, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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; In-silico analysis, which includes splice predictors and evolutionary conservation, is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 25622170, 25590586, 21250552, 21539471, 20358615, 23578821, 2004100, 10767004, 7747785, 18423521, 34930662, 34324503) -

May 01, 2017

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.58

BayesDel_noAF

Pathogenic

0.60

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.99

.;.;.;D;D;D

Eigen

Pathogenic

0.88

Eigen_PC

Pathogenic

0.80

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Pathogenic

0.99

D;.;D;D;D;.

M_CAP

Pathogenic

0.97

MetaRNN

Pathogenic

0.95

D;D;D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.3

.;.;.;M;.;.

PrimateAI

Pathogenic

0.89

PROVEAN

Pathogenic

-6.2

D;D;D;D;D;D

REVEL

Pathogenic

0.98

Sift

Pathogenic

0.0

D;D;D;D;D;D

Sift4G

Pathogenic

0.0010

D;D;D;D;D;D

Polyphen

1.0, 0.99

.;.;.;D;D;.

Vest4

0.95

MVP

1.0

ClinPred

1.0

GERP RS

4.3

Varity_R

0.91

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

1.0

SpliceAI score (max)

0.31

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.31

Position offset: -1

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over