rs1208782432

Variant names:

• chr6-10404734-C-T
• rs1208782432
• NM_001372066.1:c.544G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001372066.1(TFAP2A):​c.544G>A​(p.Val182Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,742 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TFAP2A NM_001372066.1 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 2.32
• Publications: 1 publications found

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

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001372066.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TFAP2A	NM_001372066.1	MANE Select	c.544G>A	p.Val182Met	missense	Exon 4 of 7	NP_001358995.1
	TFAP2A	NM_001042425.3		c.526G>A	p.Val176Met	missense	Exon 4 of 7	NP_001035890.1
	TFAP2A	NM_001032280.3		c.520G>A	p.Val174Met	missense	Exon 4 of 7	NP_001027451.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TFAP2A	ENST00000379613.10	TSL:1 MANE Select	c.544G>A	p.Val182Met	missense	Exon 4 of 7	ENSP00000368933.5
	TFAP2A	ENST00000379608.9	TSL:1	c.520G>A	p.Val174Met	missense	Exon 4 of 7	ENSP00000368928.3
	TFAP2A	ENST00000466073.5	TSL:1	c.538G>A	p.Val180Met	missense	Exon 4 of 6	ENSP00000417495.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000399 AC: 1 AN: 250904 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000883

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461742 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727182

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53406

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111896

Other (OTH) AF: 0.00 AC: 0 AN: 60392

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	3	-	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.43	T
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Uncertain	0.86	D
M_CAP	Pathogenic	0.66	D
MetaRNN	Uncertain	0.51	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Benign	0.64	N
PhyloP100		2.3
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-1.3	N
REVEL	Uncertain	0.54
Sift	Benign	0.054	T
Sift4G	Benign	0.097	T
Polyphen		0.99	D
Vest4		0.53
MutPred		0.21		Loss of ubiquitination at K176 (P = 0.0583)
MVP		0.85
ClinPred		0.75	D
GERP RS		5.5
PromoterAI		0.00040	Neutral
Varity_R		0.26
Mutation Taster		=76/24	polymorphism

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

Other links and lift over

dbSNP: rs1208782432; hg19: chr6-10404967;