rs377390031
Positions:
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP2BP6BS2
The NM_001110556.2(FLNA):c.4060G>A(p.Asp1354Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000121 in 1,209,118 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 45 hemizygotes in GnomAD. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.000063 ( 0 hom., 1 hem., cov: 25)
Exomes 𝑓: 0.00013 ( 0 hom. 44 hem. )
Consequence
FLNA
NM_001110556.2 missense
NM_001110556.2 missense
Scores
1
9
7
Clinical Significance
Conservation
PhyloP100: 1.05
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 Likely_benign. Variant got -4 ACMG points.
PP2
?
Missense variant where missense usually causes diseases, FLNA
BP6
?
Variant X-154359566-C-T is Benign according to our data. Variant chrX-154359566-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 190193.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=3}.
BS2
?
High Hemizygotes in GnomAdExome4 at 44 XL gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FLNA | NM_001110556.2 | c.4060G>A | p.Asp1354Asn | missense_variant | 24/48 | ENST00000369850.10 | |
FLNA | NM_001456.4 | c.4060G>A | p.Asp1354Asn | missense_variant | 24/47 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FLNA | ENST00000369850.10 | c.4060G>A | p.Asp1354Asn | missense_variant | 24/48 | 1 | NM_001110556.2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000626 AC: 7AN: 111903Hom.: 0 Cov.: 25 AF XY: 0.0000293 AC XY: 1AN XY: 34089
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GnomAD3 exomes AF: 0.0000388 AC: 7AN: 180302Hom.: 0 AF XY: 0.0000748 AC XY: 5AN XY: 66876
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GnomAD4 exome AF: 0.000127 AC: 139AN: 1097215Hom.: 0 Cov.: 34 AF XY: 0.000121 AC XY: 44AN XY: 362973
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GnomAD4 genome ? AF: 0.0000626 AC: 7AN: 111903Hom.: 0 Cov.: 25 AF XY: 0.0000293 AC XY: 1AN XY: 34089
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:3Benign:2
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:1Benign:1
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Jul 14, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Nov 23, 2022 | PP2 - |
Familial thoracic aortic aneurysm and aortic dissection Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 08, 2019 | The p.D1354N variant (also known as c.4060G>A), located in coding exon 23 of the FLNA gene, results from a G to A substitution at nucleotide position 4060. The aspartic acid at codon 1354 is replaced by asparagine, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species; however, asparagineis the reference amino acid in other vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Heterotopia, periventricular, X-linked dominant Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Claritas Genomics | Oct 01, 2014 | - - |
Melnick-Needles syndrome;C0265293:Frontometaphyseal dysplasia;C1844696:Oto-palato-digital syndrome, type II;C1848213:Heterotopia, periventricular, X-linked dominant Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Dec 16, 2023 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Uncertain
DEOGEN2
Uncertain
D;.;.;.;.
FATHMM_MKL
Benign
N
LIST_S2
Uncertain
D;D;.;D;D
M_CAP
Pathogenic
D
MetaRNN
Uncertain
T;T;T;T;T
MetaSVM
Uncertain
D
MutationAssessor
Uncertain
M;.;M;M;.
MutationTaster
Benign
D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;.;D;D;.
REVEL
Uncertain
Sift
Benign
D;.;D;D;.
Sift4G
Benign
T;T;T;T;T
Polyphen
D;.;B;B;.
Vest4
MVP
MPC
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at