NM_001372066.1(TFAP2A):c.766C>T (p.Arg256Trp) AND Inborn genetic diseases

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Jan 24, 2024
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV004026051.1

Allele description [Variation Report for NM_001372066.1(TFAP2A):c.766C>T (p.Arg256Trp)]

NM_001372066.1(TFAP2A):c.766C>T (p.Arg256Trp)

Genes:

LOC121740638:BRD4-independent group 4 enhancer GRCh37_chr6:10403277-10404476 [Gene]
TFAP2A-AS2:TFAP2A antisense RNA 2 [Gene - OMIM - HGNC]
TFAP2A:transcription factor AP-2 alpha [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

6p24.3

Genomic location:

Preferred name:

NM_001372066.1(TFAP2A):c.766C>T (p.Arg256Trp)

Other names:

NM_003220.2:c.760C>T

HGVS:

NC_000006.12:g.10404512G>A
NG_016151.1:g.20053C>T
NG_075700.1:g.457G>A
NM_001032280.3:c.742C>T
NM_001042425.3:c.748C>T
NM_001372066.1:c.766C>TMANE SELECT
NP_001027451.1:p.Arg248Trp
NP_001035890.1:p.Arg250Trp
NP_001358995.1:p.Arg256Trp
NC_000006.11:g.10404745G>A
NR_145448.1:n.11G>A

Protein change:

R248W

Links:

dbSNP: rs151344528

NCBI 1000 Genomes Browser:

rs151344528

Molecular consequence:

NM_001032280.3:c.742C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001042425.3:c.748C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001372066.1:c.766C>T - missense variant - [Sequence Ontology: SO:0001583]
NR_145448.1:n.11G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:: Inborn genetic diseases
Identifiers:: MeSH: D030342; MedGen: C0950123

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004964306	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Jan 24, 2024)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 21204207, 23578821, 37409559 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004964306

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Jan 24, 2024)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Genotype-phenotype analysis of the branchio-oculo-facial syndrome.

Milunsky JM, Maher TM, Zhao G, Wang Z, Mulliken JB, Chitayat D, Clemens M, Stalker HJ, Bauer M, Burch M, Chénier S, Cunningham ML, Drack AV, Janssens S, Karlea A, Klatt R, Kini U, Klein O, Lachmeijer AM, Megarbane A, Mendelsohn NJ, Meschino WS, et al.

Am J Med Genet A. 2011 Jan;155A(1):22-32. doi: 10.1002/ajmg.a.33783.

PubMed [citation]

PMID:: 21204207

Analysis of TFAP2A mutations in Branchio-Oculo-Facial Syndrome indicates functional complexity within the AP-2α DNA-binding domain.

Li H, Sheridan R, Williams T.

Hum Mol Genet. 2013 Aug 15;22(16):3195-206. doi: 10.1093/hmg/ddt173. Epub 2013 Apr 10.

PubMed [citation]

PMID:: 23578821
PMCID:: PMC3723307

See all PubMed Citations (3)

Details of each submission

From Ambry Genetics, SCV004964306.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

The c.760C>T (p.R254W) alteration is located in exon 4 (coding exon 4) of the TFAP2A gene. This alteration results from a C to T substitution at nucleotide position 760, causing the arginine (R) at amino acid position 254 to be replaced by a tryptophan (W). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant was reported in multiple individuals who met clinical criteria for Branchiooculofacial syndrome, including two de novo occurrences (Milunsky, 2011). Another alteration at the same codon, TFAP2A c.761G>A (p.R254Q), has been detected de novo in an individual with features consistent with Branchiooculofacial syndrome (Ambry internal data). This amino acid position is highly conserved in available vertebrate species. Functional and structural analyses of p.R254W have demonstrated both reduced luciferase activity and DNA binding ability (Li, 2013; Liu, 2023). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: May 7, 2024

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