rs1557177751
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP2PP3
The NM_001110556.2(FLNA):c.3455C>T(p.Ala1152Val) variant causes a missense change. 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 Uncertain significance (★).
Frequency
Genomes: not found (cov: 25)
Consequence
FLNA
NM_001110556.2 missense
NM_001110556.2 missense
Scores
1
12
4
Clinical Significance
Conservation
PhyloP100: 6.72
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 Uncertain_significance. Variant got 4 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, 0.754
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FLNA | NM_001110556.2 | c.3455C>T | p.Ala1152Val | missense_variant | 22/48 | ENST00000369850.10 | |
FLNA | NM_001456.4 | c.3455C>T | p.Ala1152Val | missense_variant | 22/47 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FLNA | ENST00000369850.10 | c.3455C>T | p.Ala1152Val | missense_variant | 22/48 | 1 | NM_001110556.2 |
Frequencies
GnomAD3 genomes ? Cov.: 25
GnomAD3 genomes
?
Cov.:
25
GnomAD4 exome Cov.: 34
GnomAD4 exome
Cov.:
34
GnomAD4 genome ? Cov.: 25
GnomAD4 genome
?
Cov.:
25
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
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 | Invitae | Nov 27, 2017 | This sequence change replaces alanine with valine at codon 1152 of the FLNA protein (p.Ala1152Val). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and valine. 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. 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 C0"). This variant has not been reported in the literature in individuals with FLNA-related disease. This variant is not present in population databases (ExAC no frequency). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Benign
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Uncertain
D;.;.;.;.
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;.;D;D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D;D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Benign
L;.;L;L;.
MutationTaster
Benign
D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;.;D;D;.
REVEL
Uncertain
Sift
Benign
T;.;T;T;.
Sift4G
Uncertain
D;D;D;D;T
Polyphen
P;.;D;D;.
Vest4
MutPred
Loss of ubiquitination at K1151 (P = 0.0853);.;Loss of ubiquitination at K1151 (P = 0.0853);Loss of ubiquitination at K1151 (P = 0.0853);.;
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
DS_AG_spliceai
Position offset: 1
Find out detailed SpliceAI scores and Pangolin per-transcript scores at