rs797045163

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

Scores

14
1
2
Splicing: ADA: 0.9999
2

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 7.85
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 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
FLNANM_001110556.2 linkuse as main transcriptc.622G>C p.Gly208Arg missense_variant, splice_region_variant 3/48 ENST00000369850.10 NP_001104026.1 P21333-1Q60FE5Q6NXF2
FLNANM_001456.4 linkuse as main transcriptc.622G>C p.Gly208Arg missense_variant, splice_region_variant 3/47 NP_001447.2 P21333-2Q60FE5Q6NXF2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
FLNAENST00000369850.10 linkuse as main transcriptc.622G>C p.Gly208Arg missense_variant, splice_region_variant 3/481 NM_001110556.2 ENSP00000358866.3 P21333-1

Frequencies

GnomAD3 genomes
Cov.:
24
GnomAD4 exome
Cov.:
33
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 providedliterature onlyOMIMJun 01, 2015- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.69
D
BayesDel_noAF
Pathogenic
0.75
CADD
Pathogenic
33
DANN
Benign
0.91
DEOGEN2
Pathogenic
0.93
D;.;.;.;.
FATHMM_MKL
Uncertain
0.91
D
LIST_S2
Pathogenic
1.0
D;D;.;D;D
M_CAP
Pathogenic
0.82
D
MetaRNN
Pathogenic
0.93
D;D;D;D;D
MetaSVM
Pathogenic
1.0
D
MutationAssessor
Pathogenic
3.0
M;.;M;M;.
PrimateAI
Pathogenic
0.92
D
PROVEAN
Pathogenic
-7.0
D;.;D;D;.
REVEL
Pathogenic
0.89
Sift
Pathogenic
0.0
D;.;D;D;.
Sift4G
Pathogenic
0.0010
D;D;D;D;D
Polyphen
1.0
D;.;D;D;.
Vest4
0.90
MutPred
0.59
Gain of solvent accessibility (P = 0.0456);.;Gain of solvent accessibility (P = 0.0456);Gain of solvent accessibility (P = 0.0456);.;
MVP
1.0
MPC
3.0
ClinPred
1.0
D
GERP RS
5.1
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.8
Varity_R
0.93
gMVP
0.92

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.95
SpliceAI score (max)
0.31
Details are displayed if max score is > 0.2
DS_DG_spliceai
0.31
Position offset: -16
DS_DL_spliceai
0.23
Position offset: 0

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: rs797045163; hg19: chrX-153596210; API