rs1554728033
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Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1PM2
The NM_014425.5(INVS):c.1571+2dup variant causes a splice donor change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: not found (cov: 31)
Exomes 𝑓: 7.0e-7 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
INVS
NM_014425.5 splice_donor
NM_014425.5 splice_donor
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 7.70
Genes affected
INVS (HGNC:17870): (inversin) This gene encodes a protein containing multiple ankyrin domains and two IQ calmodulin-binding domains. The encoded protein may function in renal tubular development and function, and in left-right axis determination. This protein interacts with nephrocystin and infers a connection between primary cilia function and left-right axis determination. A similar protein in mice interacts with calmodulin. Mutations in this gene have been associated with nephronophthisis type 2. Multiple transcript variants encoding distinct isoforms have been identified for this gene. [provided by RefSeq, May 2012]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 10 ACMG points.
PVS1
Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
PM2
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
INVS | NM_014425.5 | c.1571+2dup | splice_donor_variant | ENST00000262457.7 | NP_055240.2 | |||
INVS | NM_001318381.2 | c.1283+2dup | splice_donor_variant | NP_001305310.1 | ||||
INVS | NM_001318382.2 | c.593+2dup | splice_donor_variant | NP_001305311.1 | ||||
INVS | NR_134606.2 | n.1769+2dup | splice_donor_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
INVS | ENST00000262457.7 | c.1571+2dup | splice_donor_variant | 1 | NM_014425.5 | ENSP00000262457 | A2 | |||
INVS | ENST00000262456.6 | c.1571+2dup | splice_donor_variant | 5 | ENSP00000262456 | P4 |
Frequencies
GnomAD3 genomes Cov.: 31
GnomAD3 genomes
Cov.:
31
GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 7.04e-7 AC: 1AN: 1421120Hom.: 0 Cov.: 27 AF XY: 0.00 AC XY: 0AN XY: 709162
GnomAD4 exome
Data not reliable, filtered out with message: AS_VQSR
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1
AN:
1421120
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27
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0
AN XY:
709162
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GnomAD4 genome Cov.: 31
GnomAD4 genome
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31
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Nephronophthisis Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jul 10, 2023 | This sequence change falls in intron 11 of the INVS gene. It does not directly change the encoded amino acid sequence of the INVS protein. It affects a nucleotide within the consensus splice site. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with INVS-related conditions (Invitae). ClinVar contains an entry for this variant (Variation ID: 531626). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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. - |
Computational scores
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Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DL_spliceai
Position offset: -1
Find out detailed SpliceAI scores and Pangolin per-transcript scores at