chrX-154352311-GCTGA-G
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001110556.2(FLNA):c.6635_6638delTCAG(p.Val2212AlafsTer2) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_001110556.2 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
FLNA | NM_001110556.2 | c.6635_6638delTCAG | p.Val2212AlafsTer2 | frameshift_variant | Exon 41 of 48 | ENST00000369850.10 | NP_001104026.1 | |
FLNA | NM_001456.4 | c.6611_6614delTCAG | p.Val2204AlafsTer2 | frameshift_variant | Exon 40 of 47 | NP_001447.2 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 25
GnomAD4 genome Cov.: 25
ClinVar
Submissions by phenotype
not provided Pathogenic:2
The c.6611_6614delTCAG ( or c.6635delTCAG due to use of alternate transcript) mutation in the FLNA gene has previously been reported in association with FLNA-disorder in a 42-year-old female with ventricular septal defects and aortic regurgitation, surgically corrected ventricular septal defect, bilateral PH and enlarged retrocerebellar space (de Wit MC et al., 2011). This individuals family history revealed her mother died of rupture of aorta, sibling with mild aortic regurgitation, and the patient had a healthy son (De Wit et al., 2011). This mutation causes a shift in reading frame starting at codon Valine 2204, changing it to an Alanine, and creating a premature stop codon at position 2 of the new reading frame, denoted p.Val2204AlafsX2. This mutation is expected to result in either an abnormal, truncated protein product or loss of protein from this allele through nonsense-mediated mRNA decay. Other frameshift mutations in the FLNA gene have been reported in association with FLNA-related disorder. Furthermore, the c.6611_6614delTCAG mutation was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. In summary, c.6611_6614delTCAG in the FLNA gene is interpreted as a disease-causing mutation. -
FLNA: PVS1, PM2, PS4:Supporting -
Melnick-Needles syndrome;C0265293:Frontometaphyseal dysplasia;C1844696:Oto-palato-digital syndrome, type II;C1848213:Heterotopia, periventricular, X-linked dominant Pathogenic:1
This sequence change creates a premature translational stop signal (p.Val2204Alafs*2) in the FLNA gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in FLNA are known to be pathogenic (PMID: 16684786, 20730588, 26471271). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with periventricular heterotopia (PMID: 20730588). ClinVar contains an entry for this variant (Variation ID: 190179). For these reasons, this variant has been classified as Pathogenic. -
Heterotopia, periventricular, X-linked dominant Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at