rs28935473
Variant summary
Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM2PP2PP3_ModeratePP5_Very_Strong
The NM_001110556.2(FLNA):c.3596C>T(p.Ser1199Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. S1199S) has been classified as Benign.
Frequency
Genomes: not found (cov: 25)
Consequence
FLNA
NM_001110556.2 missense
NM_001110556.2 missense
Scores
7
8
2
Clinical Significance
Conservation
PhyloP100: 9.89
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 Pathogenic. Variant got 13 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP2
?
Missense variant where missense usually causes diseases, FLNA
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.923
PP5
?
Variant X-154360199-G-A is Pathogenic according to our data. Variant chrX-154360199-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 11759.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154360199-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FLNA | NM_001110556.2 | c.3596C>T | p.Ser1199Leu | missense_variant | 22/48 | ENST00000369850.10 | |
FLNA | NM_001456.4 | c.3596C>T | p.Ser1199Leu | missense_variant | 22/47 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FLNA | ENST00000369850.10 | c.3596C>T | p.Ser1199Leu | missense_variant | 22/48 | 1 | NM_001110556.2 |
Frequencies
GnomAD3 genomes ? Cov.: 25
GnomAD3 genomes
?
Cov.:
25
GnomAD4 exome Cov.: 33
GnomAD4 exome
Cov.:
33
GnomAD4 genome ? Cov.: 25
GnomAD4 genome
?
Cov.:
25
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:4Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Melnick-Needles syndrome Pathogenic:3Other:1
not provided, no classification provided | literature only | GeneReviews | - | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Genetics and Molecular Pathology, SA Pathology | Nov 02, 2022 | The FLNA c.3596C>T variant is classified as a LIKELY PATHOGENIC variant (PS4, PM2, PP3) The variant is a single nucleotide change in exon 22/48 of the FLNA gene, which is predicted to change the amino acid serine at position 1199 in the protein to leucine. This is a recurrent pathogenic variant in the FLNA gene, and has been previously reported in many individuals affected with Melnick Needle syndrome in both states of hemizygous (in males, more severe) and heterozygous (in females, less severe) (PMID: 12612583, 20186808 26404489) (PS4). The variant is in dbSNP (rs28935473) but is absent from population databases (PM2). The variant has been reported in ClinVar as pathogenic (Variation ID: 11759). The variant has been reported in HGMD as disease causing (Accession no.: CM030673). Computational predictions support a deleterious effect on the gene or gene product (PP3). Clinical review is recommended. *Hemizygous mutation in males causes more severe phenotypes. Monoallelic mutations in females may cause disease with less severe, later onset than males. **'Limited' Gene-disease association with Vascular abnormality and hyperflexi joint (EDS-like) (PMID: 29334594) (AusPanelApp 2022). - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Apr 01, 2003 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Claritas Genomics | Dec 17, 2008 | - - |
Melnick-Needles syndrome;C0265293:Frontometaphyseal dysplasia;C1844696:Oto-palato-digital syndrome, type II;C1848213:Heterotopia, periventricular, X-linked dominant Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 23, 2016 | This variant has been reported in the literature in more than 6 individuals affected with Melnick Needles syndrome, with several of them being reported as de novo events (PMID: 12612583, 20186808, 26404489). ClinVar contains an entry for this variant (Variation ID: 11759). In summary, this variant is a well established pathogenic rare missense change that has been reported in multiple affected individuals. For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C65"). This variant is not present in population databases (ExAC no frequency). This sequence change replaces serine with leucine at codon 1199 of the FLNA protein (p.Ser1199Leu). The serine residue is highly conserved and there is a large physicochemical difference between serine and leucine. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Uncertain
Dann
Uncertain
DEOGEN2
Uncertain
D;.;.;.;.
FATHMM_MKL
Uncertain
D
LIST_S2
Pathogenic
D;D;.;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Uncertain
M;.;M;M;.
MutationTaster
Benign
A;A;A;A
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;.;D;D;.
REVEL
Pathogenic
Sift
Uncertain
D;.;D;D;.
Sift4G
Benign
T;T;T;T;T
Polyphen
D;.;P;P;.
Vest4
MutPred
Loss of disorder (P = 0.0888);.;Loss of disorder (P = 0.0888);Loss of disorder (P = 0.0888);.;
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at