6-10398417-T-C

Variant names:

• chr6-10398417-T-C
• rs1554110673
• NM_001372066.1:c.1320A>G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PM4 PP5_Moderate

The NM_001372066.1(TFAP2A):​c.1320A>G​(p.Ter440Trpext*?) variant causes a stop lost change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TFAP2A NM_001372066.1 stop_lost
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.81
• Publications: 0 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: Orphanet, G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Stoplost variant in NM_001372066.1 Downstream stopcodon found after 28 codons.
• PP5: Variant 6-10398417-T-C is Pathogenic according to our data. Variant chr6-10398417-T-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 547805.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TFAP2A	NM_001372066.1	c.1320A>G	p.Ter440Trpext*?	stop_lost	Exon 7 of 7	ENST00000379613.10	NP_001358995.1
TFAP2A	NM_001042425.3	c.1302A>G	p.Ter434Trpext*?	stop_lost	Exon 7 of 7		NP_001035890.1
TFAP2A	NM_001032280.3	c.1296A>G	p.Ter432Trpext*?	stop_lost	Exon 7 of 7		NP_001027451.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TFAP2A	ENST00000379613.10	c.1320A>G	p.Ter440Trpext*?	stop_lost	Exon 7 of 7	1	NM_001372066.1	ENSP00000368933.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 38

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Branchiooculofacial syndrome Pathogenic:1

Nov 01, 2016

Center for Human Genetics, Inc, Center for Human Genetics, Inc

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.018	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	19
DANN	Benign	0.87
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.96
FATHMM_MKL	Pathogenic	0.99	D
PhyloP100		7.8
Vest4		0.27
GERP RS		5.2
Mutation Taster		=10/190	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: rs1554110673; hg19: chr6-10398650;