rs377330443
Positions:
Variant summary
Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2
The NM_001110556.2(FLNA):c.5313+4C>T variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000421 in 1,195,884 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 171 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Genomes: 𝑓 0.00027 ( 0 hom., 3 hem., cov: 26)
Exomes 𝑓: 0.00044 ( 0 hom. 168 hem. )
Consequence
FLNA
NM_001110556.2 splice_donor_region, intron
NM_001110556.2 splice_donor_region, intron
Scores
2
Splicing: ADA: 0.0005456
2
Clinical Significance
Conservation
PhyloP100: -1.51
Genes affected
FLNA (HGNC:3754): (filamin A) The protein encoded by this gene is an actin-binding protein that crosslinks actin filaments and links actin filaments to membrane glycoproteins. The encoded protein is involved in remodeling the cytoskeleton to effect changes in cell shape and migration. This protein interacts with integrins, transmembrane receptor complexes, and second messengers. Defects in this gene are a cause of several syndromes, including periventricular nodular heterotopias (PVNH1, PVNH4), otopalatodigital syndromes (OPD1, OPD2), frontometaphyseal dysplasia (FMD), Melnick-Needles syndrome (MNS), and X-linked congenital idiopathic intestinal pseudoobstruction (CIIPX). Two transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Mar 2009]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -20 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.88).
BP6
?
Variant X-154354612-G-A is Benign according to our data. Variant chrX-154354612-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 213452.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154354612-G-A is described in Lovd as [Likely_benign].
BS1
?
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000274 (31/113241) while in subpopulation NFE AF= 0.000544 (29/53286). AF 95% confidence interval is 0.000389. There are 0 homozygotes in gnomad4. There are 3 alleles in male gnomad4 subpopulation. Median coverage is 26. This position pass quality control queck.
BS2
?
High Hemizygotes in GnomAd4 at 3 XL gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FLNA | NM_001110556.2 | c.5313+4C>T | splice_donor_region_variant, intron_variant | ENST00000369850.10 | |||
FLNA | NM_001456.4 | c.5289+4C>T | splice_donor_region_variant, intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FLNA | ENST00000369850.10 | c.5313+4C>T | splice_donor_region_variant, intron_variant | 1 | NM_001110556.2 |
Frequencies
GnomAD3 genomes ? AF: 0.000274 AC: 31AN: 113241Hom.: 0 Cov.: 26 AF XY: 0.0000848 AC XY: 3AN XY: 35381
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GnomAD3 exomes AF: 0.000247 AC: 37AN: 149679Hom.: 0 AF XY: 0.000214 AC XY: 10AN XY: 46749
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GnomAD4 exome AF: 0.000437 AC: 473AN: 1082643Hom.: 0 Cov.: 31 AF XY: 0.000476 AC XY: 168AN XY: 352605
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GnomAD4 genome ? AF: 0.000274 AC: 31AN: 113241Hom.: 0 Cov.: 26 AF XY: 0.0000848 AC XY: 3AN XY: 35381
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Benign:3
Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Likely benign, no assertion criteria provided | clinical testing | Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | - | - - |
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Aug 01, 2022 | FLNA: BP4, BS2 - |
not specified Benign:1
Benign, criteria provided, single submitter | clinical testing | GeneDx | Sep 04, 2014 | This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. - |
Familial thoracic aortic aneurysm and aortic dissection Benign:1
Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 23, 2019 | This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
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 | Jan 19, 2024 | - - |
FLNA-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jul 23, 2019 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Computational scores
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Name
Calibrated prediction
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Prediction
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
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Calibrated prediction
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dbscSNV1_ADA
Benign
dbscSNV1_RF
Benign
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at