rs80338841
Variant names:
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP5
The NM_001110556.2(FLNA):c.1923C>T(p.Gly641Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: not found (cov: 23)
Exomes 𝑓: 0.0000027 ( 0 hom. 0 hem. )
Failed GnomAD Quality Control
Consequence
FLNA
NM_001110556.2 synonymous
NM_001110556.2 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: -0.629
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]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 3 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant X-154364625-G-A is Pathogenic according to our data. Variant chrX-154364625-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 11770.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Pathogenic=2, not_provided=1}. Variant chrX-154364625-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| FLNA | NM_001110556.2 | c.1923C>T | p.Gly641Gly | synonymous_variant | Exon 13 of 48 | ENST00000369850.10 | NP_001104026.1 | |
| FLNA | NM_001456.4 | c.1923C>T | p.Gly641Gly | synonymous_variant | Exon 13 of 47 | NP_001447.2 |
Ensembl
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
23
GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000273 AC: 3AN: 1097512Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 363238
GnomAD4 exome
Data not reliable, filtered out with message: AS_VQSR
AF:
AC:
3
AN:
1097512
Hom.:
Cov.:
33
AF XY:
AC XY:
0
AN XY:
363238
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome
GnomAD4 genome
Cov.:
23
ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:4Uncertain:2Other:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Pathogenic:1Uncertain:1
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Oct 21, 2023 | Published functional studies demonstrate that this variant creates an upstream cryptic splice donor site and leads to abnormal gene splicing in a gene for which loss-of-function is a known mechanism of disease (Hehr et al., 2006); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 16299064, 26582918, 27535533) - |
| Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Apr 01, 2023 | FLNA: PM2:Supporting, PP3, PS3:Supporting, PS4:Supporting - |
FLNA-related periventricular nodular heterotopia Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 29, 2021 | The FLNA c.1923C>T (p.Gly641) variant is a synonymous variant that creates a novel donor splice site and that has been reported in one study in which it was found in a hemizygous state in a male child with periventricular nodular heterotopia, dysmorphic facial features, and severe constipation (Hehr et al. 2006). The variant was also identified in a heterozygous state in the proband's clinically unaffected mother who was later found to have periventricular nodular heterotopia on brain MRI performed after detection of this variant in her child. PCR amplification of cDNA from cultured lymphocytes from the proband, unaffected mother, and an unaffected brother who did not carry the variant, revealed a normal length product for all three individuals in addition to a smaller product observed for the proband and mother. This smaller product was a result of alternative splicing using the newly created donor splice site, which causes loss of the 3' segment of exon 13 resulting in a frameshift and premature stop codon at residue 681. The c.1923C>T variant is not found in the Genome Aggregation Database in a region of good sequence coverage, so the variant is presumed to be rare. Based on the collective evidence in the literature and application of the ACMG criteria, the c.1923C>T variant is classified as pathogenic for FLNA-related periventricular nodular heterotopia. - |
FLNA-related disorder Pathogenic:1
| Likely pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Jul 22, 2024 | The FLNA c.1923C>T variant is not predicted to result in an amino acid change (p.=). This variant has been reported in the hemizygous state in a male patient with periventricular nodular heterotopia (PVNH) and in his clinically asymptomatic mother who also had PVNH on MRI (Hehr et al. 2006. PubMed ID: 16299064). cDNA sequencing indicated this variant impacts mRNA splicing (Hehr et al. 2006. PubMed ID: 16299064). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as likely pathogenic. - |
Heterotopia, periventricular, X-linked dominant Pathogenic:1
| Pathogenic, no assertion criteria provided | literature only | OMIM | Aug 15, 2007 | - - |
Melnick-Needles syndrome;C0265293:Frontometaphyseal dysplasia;C1844696:Oto-palato-digital syndrome, type II;C1848213:Heterotopia, periventricular, X-linked dominant Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Oct 06, 2020 | This sequence change affects codon 641 of the FLNA mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the FLNA protein. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with clinical features of FLNA-related conditions (PMID: 16299064). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 11770). Experimental studies have shown that this variant disrupts mRNA splicing (PMID: 16299064). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Cardiac valvular dysplasia, X-linked Other:1
| not provided, no classification provided | literature only | GeneReviews | - | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DG_spliceai
Position offset: 2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at