rs797045163
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PP2PP3_ModeratePP5
The NM_001110556.2(FLNA):c.622G>C(p.Gly208Arg) variant causes a missense, splice region 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. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars).
Frequency
Genomes: not found (cov: 24)
Consequence
FLNA
NM_001110556.2 missense, splice_region
NM_001110556.2 missense, splice_region
Scores
14
1
2
Splicing: ADA: 0.9999
2
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 Likely_pathogenic. Variant got 8 ACMG points.
PM1
In a domain Calponin-homology (CH) 2 (size 103) in uniprot entity FLNA_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_001110556.2
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.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.933
PP5
Variant X-154367842-C-G is Pathogenic according to our data. Variant chrX-154367842-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 209069.Status of the report is no_assertion_criteria_provided, 0 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
FLNA | NM_001110556.2 | c.622G>C | p.Gly208Arg | missense_variant, splice_region_variant | 3/48 | ENST00000369850.10 | NP_001104026.1 | |
FLNA | NM_001456.4 | c.622G>C | p.Gly208Arg | missense_variant, splice_region_variant | 3/47 | NP_001447.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
FLNA | ENST00000369850.10 | c.622G>C | p.Gly208Arg | missense_variant, splice_region_variant | 3/48 | 1 | NM_001110556.2 | ENSP00000358866.3 |
Frequencies
GnomAD3 genomes Cov.: 24
GnomAD3 genomes
Cov.:
24
GnomAD4 exome Cov.: 33
GnomAD4 exome
Cov.:
33
GnomAD4 genome Cov.: 24
GnomAD4 genome
Cov.:
24
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: no assertion criteria provided
LINK: link
Submissions by phenotype
HETEROTOPIA, PERIVENTRICULAR NODULAR, X-LINKED DOMINANT, WITH MELNICK-NEEDLES SYNDROME Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jun 01, 2015 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Benign
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;.
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 solvent accessibility (P = 0.0456);.;Gain of solvent accessibility (P = 0.0456);Gain of solvent accessibility (P = 0.0456);.;
MVP
MPC
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DG_spliceai
Position offset: -16
DS_DL_spliceai
Position offset: 0
Find out detailed SpliceAI scores and Pangolin per-transcript scores at