rs1554110735

chr6-10398692-CTT-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_Strong PP5_Very_Strong

The NM_001372066.1(TFAP2A):c.1043_1044del(p.Lys348ArgfsTer84) variant causes a frameshift change involving the alteration of a conserved nucleotide. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TFAP2A NM_001372066.1 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 8.02

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]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.21 CDS is truncated, and there are 2 pathogenic variants in the truncated region.
• PP5: Variant 6-10398692-CTT-C is Pathogenic according to our data. Variant chr6-10398692-CTT-C is described in ClinVar as [Pathogenic]. Clinvar id is 523459.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TFAP2A	NM_001372066.1	c.1043_1044del	p.Lys348ArgfsTer84	frameshift_variant	7/7	ENST00000379613.10
TFAP2A	NM_001032280.3	c.1019_1020del	p.Lys340ArgfsTer84	frameshift_variant	7/7
TFAP2A	NM_001042425.3	c.1025_1026del	p.Lys342ArgfsTer84	frameshift_variant	7/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TFAP2A	ENST00000379613.10	c.1043_1044del	p.Lys348ArgfsTer84	frameshift_variant	7/7	1	NM_001372066.1	A1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Branchiooculofacial syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genetics Department, University Hospital of Toulouse

May 15, 2020

This null variant affecting TFAP2A gene c.1037_1038del, p.(Lys346fs*84) is absent from GnomAD and was once reported in the Clinvar database as pathogenic (SCV000747548.1) -

Amblyopia;C0014877:Esotropia;C0020534:Hypertelorism;C0023316:Lens subluxation;C0026010:Microphthalmia;C0028738:Nystagmus;C0151611:EEG abnormality;C0239234:Low-set ears;C0240063:Iris coloboma;C0240635:High palate;C0521525:Short neck;C0522214:Abnormality of visual evoked potentials;C0678230:Epicanthus Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Jan 01, 2017

- -

Computational scores

Source: dbNSFP v4.3

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

Other links and lift over

dbSNP: rs1554110735; hg19: chr6-10398925;