rs397516855
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1PM2PP5
The NM_003476.5(CSRP3):c.282-5_285del variant causes a splice acceptor, coding sequence, intron change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: not found (cov: 32)
Consequence
CSRP3
NM_003476.5 splice_acceptor, coding_sequence, intron
NM_003476.5 splice_acceptor, coding_sequence, intron
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 3.83
Genes affected
CSRP3 (HGNC:2472): (cysteine and glycine rich protein 3) This gene encodes a member of the CSRP family of LIM domain proteins, which may be involved in regulatory processes important for development and cellular differentiation. The LIM/double zinc-finger motif found in this protein is found in a group of proteins with critical functions in gene regulation, cell growth, and somatic differentiation. Mutations in this gene are thought to cause heritable forms of hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM) in humans. Alternatively spliced transcript variants with different 5' UTR, but encoding the same protein, have been found for this gene. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 11 ACMG points.
PVS1
?
Splicing variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 5.8, offset of 10, new splice context is: attcgtctatttccccaaAGccg. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 11-19186344-GGGACCTGTT-G is Pathogenic according to our data. Variant chr11-19186344-GGGACCTGTT-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 44693.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Likely_pathogenic=1}.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CSRP3 | NM_003476.5 | c.282-5_285del | splice_acceptor_variant, coding_sequence_variant, intron_variant | 4/6 | ENST00000265968.9 | ||
CSRP3 | NM_001369404.1 | c.113-5_116del | splice_acceptor_variant, coding_sequence_variant, intron_variant | 3/5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CSRP3 | ENST00000265968.9 | c.282-5_285del | splice_acceptor_variant, coding_sequence_variant, intron_variant | 4/6 | 1 | NM_003476.5 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
Bravo
AF:
ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:4
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | AiLife Diagnostics, AiLife Diagnostics | Dec 03, 2021 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Dilated cardiomyopathy 1M;C2677491:Hypertrophic cardiomyopathy 12 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jun 13, 2023 | In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 44693). This variant has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 27532257, 30847666). This variant is not present in population databases (gnomAD no frequency). This variant results in the deletion of part of exon 5 (c.282-5_285del) of the CSRP3 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in CSRP3 are known to be pathogenic (PMID: 12642359, 14567970, 16352453, 20087448, 34558151). - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Mar 08, 2012 | Variant classified as Uncertain Significance - Favor Pathogenic. The 282-5_285de lAACAGGTCC variant (CSRP3) has not been previously reported in the literature or been previously identified by our laboratory. This variant causes a deletion o f the invariant region of the splice consensus sequence and is predicted to caus e altered splicing leading to an abnormal or absent protein. The impact of loss of function variants in CSRP3 in relation to HCM is not well understood. In su mmary, although this variant may be pathogenic, additional studies are needed to fully assess its clinical significance. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at