chrX-154348850-CAG-C
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PM4PP5_Very_Strong
The NM_001110556.2(FLNA):c.7941_7942del(p.Ter2648SerfsTer101) variant causes a frameshift, stop lost change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. P2647P) has been classified as Likely benign.
Frequency
Genomes: not found (cov: 24)
Consequence
FLNA
NM_001110556.2 frameshift, stop_lost
NM_001110556.2 frameshift, stop_lost
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 6.22
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 Pathogenic. Variant got 12 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PM4
?
Frameshift in the end of transcript resulting in stoplost. Downstream stopcodon found after 2648 codons.
PP5
?
Variant X-154348850-CAG-C is Pathogenic according to our data. Variant chrX-154348850-CAG-C is described in ClinVar as [Pathogenic]. Clinvar id is 213498.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154348850-CAG-C is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FLNA | NM_001110556.2 | c.7941_7942del | p.Ter2648SerfsTer101 | frameshift_variant, stop_lost | 48/48 | ENST00000369850.10 | |
FLNA | NM_001456.4 | c.7917_7918del | p.Ter2640SerfsTer101 | frameshift_variant, stop_lost | 47/47 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FLNA | ENST00000369850.10 | c.7941_7942del | p.Ter2648SerfsTer101 | frameshift_variant, stop_lost | 48/48 | 1 | NM_001110556.2 |
Frequencies
GnomAD3 genomes ? Cov.: 24
GnomAD3 genomes
?
Cov.:
24
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome ? Cov.: 24
GnomAD4 genome
?
Cov.:
24
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Melnick-Needles syndrome;C0265293:Frontometaphyseal dysplasia;C1844696:Oto-palato-digital syndrome, type II;C1848213:Heterotopia, periventricular, X-linked dominant Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 17, 2023 | This protein extension has been observed in individual(s) with bilateral periventricular heterotopia, congenital short bowel, and additional FLNA-related conditions (PMID: 23873601, 28428218). It has also been observed to segregate with disease in related individuals. For these reasons, this variant has been classified as Pathogenic. Studies have shown that this protein extension alters FLNA gene expression (PMID: 23873601, 28428218). ClinVar contains an entry for this variant (Variation ID: 213498). This variant is also known as c.7941_7942delCT (p.2648Serext*100). This variant is not present in population databases (gnomAD no frequency). This sequence change disrupts the translational stop signal of the FLNA mRNA. It is expected to extend the length of the FLNA protein by 100 additional amino acid residues. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jan 07, 2015 | The c.7917_7918delCT mutation has been reported previously (using alternative nomenclature c.7941_7942delCT) in association with a form of X-linked periventricular nodular heterotopia (XL-PNH) in a family consisting of 2 brothers, their mother, a maternal aunt and her son, another maternal aunt and the maternal grandmother (Oegema et al., 2013). The phenotype of the brothers and male first cousin was characterized by failure to thrive, distinct facial appearance, and variable multi-organ involvement, including PNH, congenital short bowel with malrotation, wandering spleen, cardiovascular and urinary tract abnormalities (Oegema et al., 2013). Diminished FLNA protein levels were observed in the 2 affected brothers as compared to their mother, who was reported to be healthy although she carried the c.7917_7918delCT mutation (Oegema et al., 2013). Additionally, expression of mRNA was down-regulated in both brothers and their mother (Oegema et al., 2013). The other female family members carrying the mutation (maternal aunt and grandmother) demonstrated additional phenotypic variability including PNH, seizures, mitral valve prolapse, umbilical hernia, joint pain, hypertelorism, depression, anxiety, and/or a history of miscarriages (Oegema et al., 2013). This deletion destroys the natural stop codon at position 2640, replaces it with a Serine residue and extends the protein by 100 amino acids, denoted p.X2640SextX100. This mutation was not observed in approximately 6,200 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Therefore, c.7917_7918delCT is considered a pathogenic mutation. - |
Heterotopia, periventricular, X-linked dominant Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 09, 2023 | - - |
Computational scores
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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