dbSNP rs267607108: TFAP2A:p.Glu298Lys (chr6-10400587-C-T) – ACMG Classification: Likely_pathogenic (7 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2PP3_StrongPP5

The NM_001372066.1(TFAP2A):c.892G>A(p.Glu298Lys) 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. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars).

Frequency

Genomes: not found (cov: 32)

Consequence

TFAP2A
NM_001372066.1 missense, splice_region

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 7.91

Publications

4 publications found

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 Gene-Disease associations (from GenCC):

branchiooculofacial syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, G2P, Orphanet

TFAP2A links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.981

PP5

Variant 6-10400587-C-T is Pathogenic according to our data. Variant chr6-10400587-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 18465.Status of the report is no_assertion_criteria_provided, 0 stars.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TFAP2A	NM_001372066.1	MANE Select	c.892G>A	p.Glu298Lys	missense splice_region	Exon 6 of 7	NP_001358995.1	A0A6E1XE14
TFAP2A	NM_001042425.3		c.874G>A	p.Glu292Lys	missense splice_region	Exon 6 of 7	NP_001035890.1	P05549-6
TFAP2A	NM_001032280.3		c.868G>A	p.Glu290Lys	missense splice_region	Exon 6 of 7	NP_001027451.1	P05549-5

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TFAP2A	ENST00000379613.10	TSL:1 MANE Select	c.892G>A	p.Glu298Lys	missense splice_region	Exon 6 of 7	ENSP00000368933.5	A0A6E1XE14
TFAP2A	ENST00000379608.9	TSL:1	c.868G>A	p.Glu290Lys	missense splice_region	Exon 6 of 7	ENSP00000368928.3	P05549-5
TFAP2A	ENST00000466073.5	TSL:1	c.884-1882G>A		intron	N/A	ENSP00000417495.1	C1K3N0

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

Branchiooculofacial syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.54

BayesDel_noAF

Pathogenic

0.54

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.99

Eigen

Uncertain

0.68

Eigen_PC

Pathogenic

0.69

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.88

M_CAP

Pathogenic

0.36

MetaRNN

Pathogenic

0.98

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.4

PhyloP100

7.9

PrimateAI

Pathogenic

0.85

PROVEAN

Uncertain

-3.7

REVEL

Pathogenic

0.92

Sift

Uncertain

0.016

Sift4G

Uncertain

0.0070

Polyphen

0.011

Vest4

0.99

MutPred

0.93

Gain of ubiquitination at E296 (P = 0.0138)

MVP

0.99

ClinPred

0.99

GERP RS

5.3

Varity_R

0.72

Mutation Taster

=13/87

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over