rs28935470
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1PM2PP2PP3_StrongPP5_Very_Strong
The NM_001110556.2(FLNA):c.760G>A(p.Glu254Lys) 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 Pathogenic (★★).
Frequency
Genomes: not found (cov: 24)
Consequence
FLNA
NM_001110556.2 missense
NM_001110556.2 missense
Scores
10
6
1
Clinical Significance
Conservation
PhyloP100: 7.85
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 17 ACMG points.
PM1
In a domain Calponin-homology (CH) 2 (size 103) in uniprot entity FLNA_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_001110556.2
PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), FLNA. . Gene score misZ 3.7802 (greater than the threshold 3.09). GenCC has associacion of gene with X-linked Ehlers-Danlos syndrome, terminal osseous dysplasia-pigmentary defects syndrome, FG syndrome 2, frontometaphyseal dysplasia, heterotopia, periventricular, X-linked dominant, Melnick-Needles syndrome, otopalatodigital syndrome type 2, periventricular nodular heterotopia, otopalatodigital syndrome type 1, intestinal pseudoobstruction, neuronal, chronic idiopathic, X-linked, familial thoracic aortic aneurysm and aortic dissection, congenital short bowel syndrome, frontometaphyseal dysplasia 1, cardiac valvular dysplasia, X-linked.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.96
PP5
Variant X-154367505-C-T is Pathogenic according to our data. Variant chrX-154367505-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 11756.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154367505-C-T is described in Lovd as [Pathogenic]. Variant chrX-154367505-C-T is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
FLNA | NM_001110556.2 | c.760G>A | p.Glu254Lys | missense_variant | 5/48 | ENST00000369850.10 | NP_001104026.1 | |
FLNA | NM_001456.4 | c.760G>A | p.Glu254Lys | missense_variant | 5/47 | NP_001447.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
FLNA | ENST00000369850.10 | c.760G>A | p.Glu254Lys | missense_variant | 5/48 | 1 | NM_001110556.2 | ENSP00000358866.3 |
Frequencies
GnomAD3 genomes Cov.: 24
GnomAD3 genomes
Cov.:
24
GnomAD4 exome Cov.: 32
GnomAD4 exome
Cov.:
32
GnomAD4 genome Cov.: 24
GnomAD4 genome
Cov.:
24
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:3
Likely pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Feb 11, 2015 | - - |
Oto-palato-digital syndrome, type II Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 15, 2009 | - - |
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 | Labcorp Genetics (formerly Invitae), Labcorp | Feb 10, 2022 | This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 254 of the FLNA protein (p.Glu254Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with otopalatodigital spectrum disorders (PMID: 12612583). ClinVar contains an entry for this variant (Variation ID: 11756). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt FLNA protein function. Experimental studies have shown that this missense change affects FLNA function (PMID: 19773341, 21620354). For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Pathogenic
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;.
PrimateAI
Pathogenic
D
PROVEAN
Uncertain
D;.;D;D;.
REVEL
Pathogenic
Sift
Uncertain
D;.;D;D;.
Sift4G
Uncertain
D;D;D;D;D
Polyphen
D;.;D;D;.
Vest4
MutPred
Gain of ubiquitination at E254 (P = 0.0211);.;Gain of ubiquitination at E254 (P = 0.0211);Gain of ubiquitination at E254 (P = 0.0211);.;
MVP
MPC
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
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