chrX-154362500-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2

The NM_001110556.2(FLNA):​c.2483G>A​(p.Arg828His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000198 in 1,210,143 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 12 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R828P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000018 ( 0 hom., 2 hem., cov: 24)
Exomes 𝑓: 0.000020 ( 0 hom. 10 hem. )

Consequence

FLNA
NM_001110556.2 missense

Scores

5
12

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 1.71
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 -5 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.32434303).
BS2
High Hemizygotes in GnomAd4 at 2 XL gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
FLNANM_001110556.2 linkc.2483G>A p.Arg828His missense_variant Exon 17 of 48 ENST00000369850.10 NP_001104026.1 P21333-1Q60FE5Q6NXF2
FLNANM_001456.4 linkc.2483G>A p.Arg828His missense_variant Exon 17 of 47 NP_001447.2 P21333-2Q60FE5Q6NXF2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
FLNAENST00000369850.10 linkc.2483G>A p.Arg828His missense_variant Exon 17 of 48 1 NM_001110556.2 ENSP00000358866.3 P21333-1

Frequencies

GnomAD3 genomes
AF:
0.0000177
AC:
2
AN:
112946
Hom.:
0
Cov.:
24
AF XY:
0.0000570
AC XY:
2
AN XY:
35086
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000929
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000188
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.0000201
AC:
22
AN:
1097197
Hom.:
0
Cov.:
33
AF XY:
0.0000276
AC XY:
10
AN XY:
362905
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000284
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000185
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000190
Gnomad4 OTH exome
AF:
0.0000434
GnomAD4 genome
AF:
0.0000177
AC:
2
AN:
112946
Hom.:
0
Cov.:
24
AF XY:
0.0000570
AC XY:
2
AN XY:
35086
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.0000929
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000188
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000378
EpiCase
AF:
0.000164
EpiControl
AF:
0.00

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Uncertain:1
Aug 17, 2024
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Melnick-Needles syndrome;C0265293:Frontometaphyseal dysplasia;C1844696:Oto-palato-digital syndrome, type II;C1848213:Heterotopia, periventricular, X-linked dominant Uncertain:1
Jan 29, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 828 of the FLNA protein (p.Arg828His). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with FLNA-related conditions. ClinVar contains an entry for this variant (Variation ID: 567520). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt FLNA protein function with a negative predictive value of 95%. 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.17
BayesDel_addAF
Benign
0.0055
T
BayesDel_noAF
Benign
-0.23
CADD
Benign
20
DANN
Uncertain
0.98
DEOGEN2
Uncertain
0.50
T;.;.;.;.
FATHMM_MKL
Benign
0.36
N
LIST_S2
Benign
0.65
T;T;.;T;T
M_CAP
Benign
0.066
D
MetaRNN
Benign
0.32
T;T;T;T;T
MetaSVM
Uncertain
-0.21
T
MutationAssessor
Benign
0.12
N;.;N;N;.
PrimateAI
Uncertain
0.52
T
PROVEAN
Benign
-1.4
N;.;N;N;.
REVEL
Uncertain
0.43
Sift
Benign
0.45
T;.;T;T;.
Sift4G
Benign
0.35
T;T;T;T;T
Polyphen
0.99
D;.;B;B;.
Vest4
0.28
MutPred
0.54
Loss of catalytic residue at R828 (P = 0.0676);.;Loss of catalytic residue at R828 (P = 0.0676);Loss of catalytic residue at R828 (P = 0.0676);.;
MVP
0.94
MPC
0.65
ClinPred
0.60
D
GERP RS
4.9
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.22
gMVP
0.25

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: rs1347740802; hg19: chrX-153590868; COSMIC: COSV61044115; COSMIC: COSV61044115; API