6-10404526-A-G

Position:

• chr6-10404526-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PP3_Strong PP5_Moderate

The NM_001372066.1(TFAP2A):​c.752T>C​(p.Leu251Pro) 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 Pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: TFAP2A NM_001372066.1 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 8.85

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]

ACMG classification

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, 0.99
• PP5: Variant 6-10404526-A-G is Pathogenic according to our data. Variant chr6-10404526-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 807514.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr6-10404526-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TFAP2A	NM_001372066.1	c.752T>C	p.Leu251Pro	missense_variant	4/7	ENST00000379613.10	NP_001358995.1
TFAP2A	NM_001042425.3	c.734T>C	p.Leu245Pro	missense_variant	4/7		NP_001035890.1
TFAP2A	NM_001032280.3	c.728T>C	p.Leu243Pro	missense_variant	4/7		NP_001027451.1
TFAP2A-AS2	NR_145448.1	n.25A>G		non_coding_transcript_exon_variant	1/1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TFAP2A	ENST00000379613.10	c.752T>C	p.Leu251Pro	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

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Branchiooculofacial syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Jan 17, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.59	D
BayesDel_noAF	Pathogenic	0.61
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	.;.;.;D;D;D
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D;.;D;D;D;.
M_CAP	Pathogenic	0.82	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D
MetaSVM	Uncertain	-0.0044	T
MutationAssessor	Pathogenic	3.4	.;.;.;M;.;.
PrimateAI	Pathogenic	0.93	D
PROVEAN	Pathogenic	-6.1	D;D;D;D;D;D
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D;D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D
Polyphen		1.0, 1.0	.;.;.;D;D;.
Vest4		0.99
MutPred		0.96		.;.;.;Gain of sheet (P = 0.0221);Gain of sheet (P = 0.0221);.;
MVP		1.0
ClinPred		1.0	D
GERP RS		4.3
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

Other links and lift over

dbSNP: rs1581262652; hg19: chr6-10404759;