rs727503930
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PP2PP3BP6BS2
The NM_001110556.2(FLNA):c.7172G>A(p.Arg2391His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000768 in 1,210,274 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 36 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. R2391R) has been classified as Likely benign.
Frequency
Consequence
NM_001110556.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FLNA | NM_001110556.2 | c.7172G>A | p.Arg2391His | missense_variant | 45/48 | ENST00000369850.10 | |
FLNA | NM_001456.4 | c.7148G>A | p.Arg2383His | missense_variant | 44/47 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FLNA | ENST00000369850.10 | c.7172G>A | p.Arg2391His | missense_variant | 45/48 | 1 | NM_001110556.2 |
Frequencies
GnomAD3 genomes ? AF: 0.00000887 AC: 1AN: 112683Hom.: 0 Cov.: 25 AF XY: 0.00 AC XY: 0AN XY: 34853
GnomAD3 exomes AF: 0.0000716 AC: 13AN: 181611Hom.: 0 AF XY: 0.0000445 AC XY: 3AN XY: 67481
GnomAD4 exome AF: 0.0000838 AC: 92AN: 1097591Hom.: 0 Cov.: 31 AF XY: 0.0000992 AC XY: 36AN XY: 363053
GnomAD4 genome ? AF: 0.00000887 AC: 1AN: 112683Hom.: 0 Cov.: 25 AF XY: 0.00 AC XY: 0AN XY: 34853
ClinVar
Submissions by phenotype
not provided Uncertain:3Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Mar 08, 2022 | The FLNA c.7148G>A; p.Arg2383His variant (rs727503930) is reported in the literature in an individual affected with otopalatodigital syndrome; however, the variant was detected in the patient’s unaffected mother who was shown to have random X chromosome inactivation (Moutton 2016). This variant is also reported in ClinVar (Variation ID: 167077), and is found in the non-Finnish European population with an allele frequency of 0.015% (12/81,373 alleles, including 3 hemizygotes) in the Genome Aggregation Database. The arginine at codon 2383 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.827). However, given the lack of clinical and functional data, the significance of this variant is uncertain at this time. References: Moutton S et al. Otopalatodigital spectrum disorders: refinement of the phenotypic and mutational spectrum. J Hum Genet. 2016 Aug;61(8):693-9. PMID: 27193221. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jan 18, 2023 | - - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Feb 03, 2021 | This variant is associated with the following publications: (PMID: 27193221) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Mar 19, 2014 | - - |
Familial thoracic aortic aneurysm and aortic dissection Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 25, 2020 | The p.R2383H variant (also known as c.7148G>A), located in coding exon 43 of the FLNA gene, results from a G to A substitution at nucleotide position 7148. The arginine at codon 2383 is replaced by histidine, an amino acid with highly similar properties. This alteration, reported as p.R2391H, has been detected in a female with clinical symptoms compatible with otopalatodigital syndrome. However, the patient also exhibited atypical findings, did not exhibit skewed X-inactivation, and inherited the variant from her unaffected mother also with random X-inactivation (Moutton S et al. J Hum Genet, 2016 Aug;61:693-9). Based on data from gnomAD, the A allele has an overall frequency of 0.007% (13/181611) total alleles studied, with 3 hemizygote(s) observed. The highest observed frequency was 0.01% (12/81373) of non-Finnish European alleles. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Melnick-Needles syndrome;C0265293:Frontometaphyseal dysplasia;C1844696:Oto-palato-digital syndrome, type II;C1848213:Heterotopia, periventricular, X-linked dominant Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 03, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at