rs1557179684
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PM2PP2PP3_StrongPP5_Moderate
The NM_001110556.2(FLNA):c.415G>C(p.Gly139Arg) 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. G139G) has been classified as Likely benign.
Frequency
Genomes: not found (cov: 24)
Consequence
FLNA
NM_001110556.2 missense
NM_001110556.2 missense
Scores
14
2
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 11 ACMG points.
PM1
?
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_001110556.2
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, 0.968
PP5
?
Variant X-154368049-C-G is Pathogenic according to our data. Variant chrX-154368049-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 519881.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FLNA | NM_001110556.2 | c.415G>C | p.Gly139Arg | missense_variant | 3/48 | ENST00000369850.10 | |
FLNA | NM_001456.4 | c.415G>C | p.Gly139Arg | missense_variant | 3/47 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FLNA | ENST00000369850.10 | c.415G>C | p.Gly139Arg | missense_variant | 3/48 | 1 | NM_001110556.2 |
Frequencies
GnomAD3 genomes ? Cov.: 24
GnomAD3 genomes
?
Cov.:
24
GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome ? Cov.: 24
GnomAD4 genome
?
Cov.:
24
ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 10, 2020 | The p.G139R variant (also known as c.415G>C), located in coding exon 2 of the FLNA gene, results from a G to C substitution at nucleotide position 415. The glycine at codon 139 is replaced by arginine, an amino acid with dissimilar properties. This alteration was previously detected in a pediatric patient reported to have bilateral, diffuse nodular heterotopia, hypoplasia of the corpus callosum and other features (Srour M et al. Epilepsia. 2011;52:728-37). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
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
Pathogenic
M;.;M;M;.
MutationTaster
Benign
D;D;D;D
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D;.;D;D;.
REVEL
Pathogenic
Sift
Pathogenic
D;.;D;D;.
Sift4G
Pathogenic
D;D;D;D;D
Polyphen
D;.;D;D;.
Vest4
MutPred
Gain of MoRF binding (P = 0.0079);.;Gain of MoRF binding (P = 0.0079);Gain of MoRF binding (P = 0.0079);.;
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