6-10404511-C-T

Position:

• chr6-10404511-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_001372066.1(TFAP2A):​c.767G>A​(p.Arg256Gln) 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R256G) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TFAP2A NM_001372066.1 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 7.51

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr6-10404512-G-C is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.98
• PP5: Variant 6-10404511-C-T is Pathogenic according to our data. Variant chr6-10404511-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 522084.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TFAP2A	NM_001372066.1	c.767G>A	p.Arg256Gln	missense_variant	4/7	ENST00000379613.10	NP_001358995.1
TFAP2A	NM_001042425.3	c.749G>A	p.Arg250Gln	missense_variant	4/7		NP_001035890.1
TFAP2A	NM_001032280.3	c.743G>A	p.Arg248Gln	missense_variant	4/7		NP_001027451.1
TFAP2A-AS2	NR_145448.1	n.10C>T		non_coding_transcript_exon_variant	1/1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TFAP2A	ENST00000379613.10	c.767G>A	p.Arg256Gln	missense_variant	4/7	1	NM_001372066.1	ENSP00000368933.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Branchiooculofacial syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Oct 09, 2024	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative and loss of function are known mechanisms of disease in this gene and are associated with Branchiooculofacial syndrome. NMD predicted variants are associated with loss of function mechanism, whereas missense mutations within DNA-binding domain are linked to dominant negative mechanism (PMID: 23578821). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity (PMID: 23578821). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to glutamine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD v2 (1 heterozygote, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants (DECIPHER; PMID: 23578821, 21204207). (SP) 0702 - Other missense variants comparable to the one identified in this case have strong previous evidence for pathogenicity. p.(Arg248Trp) has been reported in at least three individuals, two of whom were de novo events. In addition, p.(Arg248Gly) has been reported in at least one de novo individual (PMID: 21204207). Both variants have been classified as likely pathogenic/pathogenic by diagnostic laboratories in ClinVar. (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported as de novo events in two affected individuals (DECIPHER) and classified as likely pathogenic by diagnostic laboratories in ClinVar. (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) (by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Likely pathogenic, criteria provided, single submitter	clinical testing	Center for Human Genetics, Inc, Center for Human Genetics, Inc	Nov 01, 2016	- -

Inborn genetic diseases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 21, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.99	.;.;.;D;D;D
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D;.;D;D;D;.
M_CAP	Pathogenic	0.95	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.4	.;.;.;M;.;.
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-3.4	D;D;D;D;D;D
REVEL	Pathogenic	0.93
Sift	Uncertain	0.011	D;D;D;D;D;D
Sift4G	Uncertain	0.0040	D;D;D;D;D;D
Polyphen		0.91, 0.98	.;.;.;P;D;.
Vest4		0.97
MutPred		0.89		.;.;.;Loss of methylation at R254 (P = 0.0348);Loss of methylation at R254 (P = 0.0348);.;
MVP		1.0
ClinPred		1.0	D
GERP RS		4.6
Varity_R		0.71

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: rs151344530; hg19: chr6-10404744;