rs151344531

Variant names:

• chr6-10402608-G-A
• rs151344531
• NM_001372066.1:c.773C>T

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_001372066.1(TFAP2A):​c.773C>T​(p.Ala258Val) 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. 12/21 in silico tools predict a damaging outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TFAP2A NM_001372066.1 missense, splice_region
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 10.0
• Publications: 8 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 Gene-Disease associations (from GenCC):

• branchiooculofacial syndrome

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

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PM1: In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_001372066.1
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.953
• PP5: Variant 6-10402608-G-A is Pathogenic according to our data. Variant chr6-10402608-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 547803.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TFAP2A	NM_001372066.1	MANE Select	c.773C>T	p.Ala258Val	missense splice_region	Exon 5 of 7	NP_001358995.1	A0A6E1XE14
	TFAP2A	NM_001042425.3		c.755C>T	p.Ala252Val	missense splice_region	Exon 5 of 7	NP_001035890.1	P05549-6
	TFAP2A	NM_001032280.3		c.749C>T	p.Ala250Val	missense splice_region	Exon 5 of 7	NP_001027451.1	P05549-5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TFAP2A	ENST00000379613.10	TSL:1 MANE Select	c.773C>T	p.Ala258Val	missense splice_region	Exon 5 of 7	ENSP00000368933.5	A0A6E1XE14
	TFAP2A	ENST00000379608.9	TSL:1	c.749C>T	p.Ala250Val	missense splice_region	Exon 5 of 7	ENSP00000368928.3	P05549-5
	TFAP2A	ENST00000466073.5	TSL:1	c.767C>T	p.Ala256Val	missense splice_region	Exon 5 of 6	ENSP00000417495.1	C1K3N0

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1454804 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 724248

African (AFR) AF: 0.00 AC: 0 AN: 33310

American (AMR) AF: 0.00 AC: 0 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26090

East Asian (EAS) AF: 0.00 AC: 0 AN: 39662

South Asian (SAS) AF: 0.00 AC: 0 AN: 86106

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53058

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5742

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1105904

Other (OTH) AF: 0.00 AC: 0 AN: 60224

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
4	-	-	Branchiooculofacial syndrome (4)
2	-	-	not provided (2)
1	-	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.35	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Uncertain	0.42	D
MutationAssessor	Pathogenic	3.4	M
PhyloP100		10
PrimateAI	Pathogenic	0.91	D
PROVEAN	Uncertain	-3.5	D
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.86
MutPred		0.85		Gain of sheet (P = 0.0344)
MVP		0.99
ClinPred		0.99	D
GERP RS		5.8
Varity_R		0.74
Mutation Taster		=0/100	disease causing (ClinVar)

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: rs151344531; hg19: chr6-10402841; COSMIC: COSV60233722; COSMIC: COSV60233722;