chrX-154348865-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP2

The NM_001110556.2(FLNA):​c.7928G>C​(p.Arg2643Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. R2643C) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 25)

Consequence

FLNA
NM_001110556.2 missense

Scores

1
8
8

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.18
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

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.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
FLNANM_001110556.2 linkuse as main transcriptc.7928G>C p.Arg2643Pro missense_variant 48/48 ENST00000369850.10
FLNANM_001456.4 linkuse as main transcriptc.7904G>C p.Arg2635Pro missense_variant 47/47

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
FLNAENST00000369850.10 linkuse as main transcriptc.7928G>C p.Arg2643Pro missense_variant 48/481 NM_001110556.2 P21333-1

Frequencies

GnomAD3 genomes
Cov.:
25
GnomAD4 exome
Cov.:
30
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 submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpOct 08, 2021In 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. This variant has not been reported in the literature in individuals affected with FLNA-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with proline at codon 2635 of the FLNA protein (p.Arg2635Pro). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and proline. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.22
BayesDel_addAF
Pathogenic
0.17
D
BayesDel_noAF
Uncertain
0.010
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.67
D;.;.;.;.
FATHMM_MKL
Benign
0.70
D
LIST_S2
Uncertain
0.97
D;D;.;D;D
M_CAP
Benign
0.077
D
MetaRNN
Uncertain
0.53
D;D;D;D;D
MetaSVM
Benign
-0.37
T
MutationAssessor
Benign
1.3
L;.;.;.;.
MutationTaster
Benign
0.95
D;D;D;D;D
PrimateAI
Benign
0.32
T
PROVEAN
Uncertain
-2.4
N;.;N;N;.
REVEL
Uncertain
0.61
Sift
Uncertain
0.017
D;.;D;D;.
Sift4G
Benign
0.092
T;T;T;T;T
Polyphen
0.010
B;.;B;B;.
Vest4
0.56
MutPred
0.64
Gain of glycosylation at S2640 (P = 0.0659);.;.;.;.;
MVP
0.95
MPC
1.3
ClinPred
0.90
D
GERP RS
3.7
Varity_R
0.82
gMVP
0.80

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

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-153577233; API