rs199917473
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Variant summary
Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP3BP6BS1BS2
The ENST00000325888.13(FLNC):c.3790+5G>A variant causes a splice donor 5th base, intron change. The variant allele was found at a frequency of 0.0000621 in 1,610,226 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.00021 ( 1 hom., cov: 32)
Exomes 𝑓: 0.000047 ( 0 hom. )
Consequence
FLNC
ENST00000325888.13 splice_donor_5th_base, intron
ENST00000325888.13 splice_donor_5th_base, intron
Scores
2
Splicing: ADA: 0.9989
2
Clinical Significance
Conservation
PhyloP100: 6.09
Genes affected
FLNC (HGNC:3756): (filamin C) This gene encodes one of three related filamin genes, specifically gamma filamin. These filamin proteins crosslink actin filaments into orthogonal networks in cortical cytoplasm and participate in the anchoring of membrane proteins for the actin cytoskeleton. Three functional domains exist in filamin: an N-terminal filamentous actin-binding domain, a C-terminal self-association domain, and a membrane glycoprotein-binding domain. Mutations in this gene are a cause of cardiopathy. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2022]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -8 ACMG points.
PP3
Multiple lines of computational evidence support a deleterious effect 4: Cadd, dbscSNV1_ADA, dbscSNV1_RF, max_spliceai [when BayesDel_noAF, Dann was below the threshold]
BP6
Variant 7-128845260-G-A is Benign according to our data. Variant chr7-128845260-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 539452.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=1, Likely_benign=1}. Variant chr7-128845260-G-A is described in Lovd as [Likely_benign].
BS1
Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00021 (32/152338) while in subpopulation EAS AF= 0.00212 (11/5178). AF 95% confidence interval is 0.00119. There are 1 homozygotes in gnomad4. There are 19 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High AC in GnomAd4 at 32 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
FLNC | NM_001458.5 | c.3790+5G>A | splice_donor_5th_base_variant, intron_variant | ENST00000325888.13 | NP_001449.3 | |||
FLNC | NM_001127487.2 | c.3790+5G>A | splice_donor_5th_base_variant, intron_variant | NP_001120959.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
FLNC | ENST00000325888.13 | c.3790+5G>A | splice_donor_5th_base_variant, intron_variant | 1 | NM_001458.5 | ENSP00000327145 | P3 | |||
FLNC | ENST00000346177.6 | c.3790+5G>A | splice_donor_5th_base_variant, intron_variant | 1 | ENSP00000344002 | A1 |
Frequencies
GnomAD3 genomes AF: 0.000210 AC: 32AN: 152220Hom.: 1 Cov.: 32
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GnomAD3 exomes AF: 0.000184 AC: 45AN: 244480Hom.: 0 AF XY: 0.000150 AC XY: 20AN XY: 133208
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GnomAD4 exome AF: 0.0000466 AC: 68AN: 1457888Hom.: 0 Cov.: 32 AF XY: 0.0000400 AC XY: 29AN XY: 725538
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GnomAD4 genome AF: 0.000210 AC: 32AN: 152338Hom.: 1 Cov.: 32 AF XY: 0.000255 AC XY: 19AN XY: 74490
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:2
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jun 23, 2022 | Identified in an individual with HCM (Cui et al., 2018); Intronic +5 splice site variant in a gene for which loss of function is a known mechanism of disease, and splice predictors support a deleterious effect; This variant is associated with the following publications: (PMID: 30411535) - |
Cardiovascular phenotype Benign:1
Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | May 25, 2021 | This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Myofibrillar myopathy 5;C3279722:Distal myopathy with posterior leg and anterior hand involvement;C4310749:Hypertrophic cardiomyopathy 26;CN239310:Dilated Cardiomyopathy, Dominant Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 25, 2024 | - - |
Computational scores
Source:
Name
Calibrated prediction
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Prediction
BayesDel_noAF
Benign
CADD
Pathogenic
DANN
Benign
Splicing
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dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DG_spliceai
Position offset: 34
DS_DL_spliceai
Position offset: -5
Find out detailed SpliceAI scores and Pangolin per-transcript scores at