rs782639698
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP2BP4BS2
The NM_001110556.2(FLNA):c.5951C>T(p.Thr1984Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000149 in 1,210,661 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 4 hemizygotes in GnomAD. In-silico tool predicts a benign 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. T1984T) 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 -4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FLNA | NM_001110556.2 | c.5951C>T | p.Thr1984Met | missense_variant | 37/48 | ENST00000369850.10 | |
FLNA | NM_001456.4 | c.5927C>T | p.Thr1976Met | missense_variant | 36/47 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FLNA | ENST00000369850.10 | c.5951C>T | p.Thr1984Met | missense_variant | 37/48 | 1 | NM_001110556.2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000354 AC: 4AN: 112975Hom.: 0 Cov.: 25 AF XY: 0.0000570 AC XY: 2AN XY: 35111
GnomAD3 exomes AF: 0.0000331 AC: 6AN: 181427Hom.: 0 AF XY: 0.0000148 AC XY: 1AN XY: 67597
GnomAD4 exome AF: 0.0000128 AC: 14AN: 1097632Hom.: 0 Cov.: 33 AF XY: 0.00000551 AC XY: 2AN XY: 363298
GnomAD4 genome ? AF: 0.0000354 AC: 4AN: 113029Hom.: 0 Cov.: 25 AF XY: 0.0000569 AC XY: 2AN XY: 35175
ClinVar
Submissions by phenotype
not provided Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jun 01, 2022 | FLNA: PP2 - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | May 30, 2023 | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Identified in association with heterotaxy and a congenital heart disease; however, detailed clinical information was not provided (Liang et al., 2020); This variant is associated with the following publications: (PMID: 32738303) - |
Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Sep 01, 2021 | The FLNA c.5927C>T; p.Thr1976Met variant (rs782639698), also known as c.5951C>T p.Thr1984Met in transcript NM_001110556.1, is reported in the literature in a cohort of individuals affected with heterotaxy syndrome, though it was not demonstrated to be disease-causing (Liang 2020). This variant is found on only seven chromosomes (7/203448 alleles, including two hemizygotes) in the Genome Aggregation Database. The threonine at codon 1976 is highly conserved, but computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.313). Due to limited information, the clinical significance of the p.Thr1976Met variant is uncertain at this time. References: Liang et al. Identification of novel candidate genes in heterotaxy syndrome patients with congenital heart diseases by whole exome sequencing. Biochim Biophys Acta Mol Basis Dis. 2020 Dec 1;1866(12):165906. PMID: 32738303. - |
Familial thoracic aortic aneurysm and aortic dissection Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 22, 2022 | The p.T1976M variant (also known as c.5927C>T), located in coding exon 35 of the FLNA gene, results from a C to T substitution at nucleotide position 5927. The threonine at codon 1976 is replaced by methionine, an amino acid with similar properties. This alteration, noted as p.T1984M, has been reported in a heterotaxy syndrome cohort (Liang S et al. Biochim Biophys Acta Mol Basis Dis, 2020 12;1866:165906). Based on data from gnomAD, the T allele has an overall frequency of <0.01% (7/203448) total alleles studied, with 2 hemizygote(s) observed. The highest observed frequency was <0.01% (1/18330) of African alleles. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated 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
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Oct 22, 2023 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at