X-154362676-C-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001110556.2(FLNA):​c.2389G>T​(p.Ala797Ser) variant causes a missense 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. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 23)

Consequence

FLNA
NM_001110556.2 missense

Scores

17

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.101
Variant links:
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 Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.061998874).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
FLNANM_001110556.2 linkc.2389G>T p.Ala797Ser missense_variant 16/48 ENST00000369850.10 NP_001104026.1 P21333-1Q60FE5Q6NXF2
FLNANM_001456.4 linkc.2389G>T p.Ala797Ser missense_variant 16/47 NP_001447.2 P21333-2Q60FE5Q6NXF2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
FLNAENST00000369850.10 linkc.2389G>T p.Ala797Ser missense_variant 16/481 NM_001110556.2 ENSP00000358866.3 P21333-1

Frequencies

GnomAD3 genomes
Cov.:
23
GnomAD4 exome
Cov.:
33
GnomAD4 genome
Cov.:
23

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 submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJun 04, 2022In 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. 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 not expected to disrupt FLNA protein function. ClinVar contains an entry for this variant (Variation ID: 948527). This variant has not been reported in the literature in individuals affected with FLNA-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 797 of the FLNA protein (p.Ala797Ser). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.071
BayesDel_addAF
Benign
-0.27
T
BayesDel_noAF
Benign
-0.63
CADD
Benign
2.4
DANN
Benign
0.51
DEOGEN2
Benign
0.36
T;.;.;.;.
FATHMM_MKL
Benign
0.13
N
LIST_S2
Benign
0.69
T;T;.;T;D
M_CAP
Benign
0.024
T
MetaRNN
Benign
0.062
T;T;T;T;T
MetaSVM
Benign
-0.94
T
MutationAssessor
Benign
-0.85
N;.;N;N;.
PrimateAI
Benign
0.35
T
PROVEAN
Benign
1.3
N;.;N;N;.
REVEL
Benign
0.19
Sift
Benign
0.88
T;.;T;T;.
Sift4G
Benign
0.89
T;T;T;T;T
Polyphen
0.0020
B;.;B;B;.
Vest4
0.18
MutPred
0.55
Gain of disorder (P = 0.0593);.;Gain of disorder (P = 0.0593);Gain of disorder (P = 0.0593);.;
MVP
0.51
MPC
0.47
ClinPred
0.063
T
GERP RS
2.9
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.3
Varity_R
0.041
gMVP
0.075

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs201073998; hg19: chrX-153591044; COSMIC: COSV61053157; COSMIC: COSV61053157; API