rs80338841
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP5
The NM_001110556.2(FLNA):c.1923C>T(p.Gly641Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_001110556.2 synonymous
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
FLNA | NM_001110556.2 | c.1923C>T | p.Gly641Gly | synonymous_variant | Exon 13 of 48 | ENST00000369850.10 | NP_001104026.1 | |
FLNA | NM_001456.4 | c.1923C>T | p.Gly641Gly | synonymous_variant | Exon 13 of 47 | NP_001447.2 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 23
GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000273 AC: 3AN: 1097512Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 363238
GnomAD4 genome Cov.: 23
ClinVar
Submissions by phenotype
not provided Pathogenic:1Uncertain:1
Published functional studies demonstrate that this variant creates an upstream cryptic splice donor site and leads to abnormal gene splicing in a gene for which loss-of-function is a known mechanism of disease (Hehr et al., 2006); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 16299064, 26582918, 27535533) -
FLNA: PM2:Supporting, PP3, PS3:Supporting, PS4:Supporting -
FLNA-related periventricular nodular heterotopia Pathogenic:1
The FLNA c.1923C>T (p.Gly641) variant is a synonymous variant that creates a novel donor splice site and that has been reported in one study in which it was found in a hemizygous state in a male child with periventricular nodular heterotopia, dysmorphic facial features, and severe constipation (Hehr et al. 2006). The variant was also identified in a heterozygous state in the proband's clinically unaffected mother who was later found to have periventricular nodular heterotopia on brain MRI performed after detection of this variant in her child. PCR amplification of cDNA from cultured lymphocytes from the proband, unaffected mother, and an unaffected brother who did not carry the variant, revealed a normal length product for all three individuals in addition to a smaller product observed for the proband and mother. This smaller product was a result of alternative splicing using the newly created donor splice site, which causes loss of the 3' segment of exon 13 resulting in a frameshift and premature stop codon at residue 681. The c.1923C>T variant is not found in the Genome Aggregation Database in a region of good sequence coverage, so the variant is presumed to be rare. Based on the collective evidence in the literature and application of the ACMG criteria, the c.1923C>T variant is classified as pathogenic for FLNA-related periventricular nodular heterotopia. -
FLNA-related disorder Pathogenic:1
The FLNA c.1923C>T variant is not predicted to result in an amino acid change (p.=). This variant has been reported in the hemizygous state in a male patient with periventricular nodular heterotopia (PVNH) and in his clinically asymptomatic mother who also had PVNH on MRI (Hehr et al. 2006. PubMed ID: 16299064). cDNA sequencing indicated this variant impacts mRNA splicing (Hehr et al. 2006. PubMed ID: 16299064). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as likely pathogenic. -
Heterotopia, periventricular, X-linked dominant Pathogenic:1
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Melnick-Needles syndrome;C0265293:Frontometaphyseal dysplasia;C1844696:Oto-palato-digital syndrome, type II;C1848213:Heterotopia, periventricular, X-linked dominant Uncertain:1
This sequence change affects codon 641 of the FLNA mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the FLNA protein. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with clinical features of FLNA-related conditions (PMID: 16299064). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 11770). Experimental studies have shown that this variant disrupts mRNA splicing (PMID: 16299064). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Cardiac valvular dysplasia, X-linked Other:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at