chr16-1526594-C-T
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Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PP3_ModeratePP5_Very_Strong
The NM_014714.4(IFT140):c.2577+25G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000148 in 1,348,606 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000015 ( 0 hom. )
Consequence
IFT140
NM_014714.4 intron
NM_014714.4 intron
Scores
2
Clinical Significance
Conservation
PhyloP100: -0.392
Genes affected
IFT140 (HGNC:29077): (intraflagellar transport 140) This gene encodes one of the subunits of the intraflagellar transport (IFT) complex A. Intraflagellar transport is involved in the genesis, resorption and signaling of primary cilia. The primary cilium is a microtubule-based sensory organelle at the surface of most quiescent mammalian cells, that receives signals from its environment, such as the flow of fluid, light or odors, and transduces those signals to the nucleus. Loss of the corresponding protein in mouse results in renal cystic disease. [provided by RefSeq, Jun 2012]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 12 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
Variant 16-1526594-C-T is Pathogenic according to our data. Variant chr16-1526594-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 523178.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
IFT140 | NM_014714.4 | c.2577+25G>A | intron_variant | ENST00000426508.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
IFT140 | ENST00000426508.7 | c.2577+25G>A | intron_variant | 5 | NM_014714.4 | P1 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 genomes
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33
GnomAD4 exome AF: 0.00000148 AC: 2AN: 1348606Hom.: 0 Cov.: 31 AF XY: 0.00000151 AC XY: 1AN XY: 662694
GnomAD4 exome
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1348606
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31
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1
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662694
Gnomad4 AFR exome
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GnomAD4 genome Cov.: 33
GnomAD4 genome
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33
Bravo
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Saldino-Mainzer syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | research | Laboratory of Medical Genetics (UMR_S 1112), INSERM/Strasbourg University | Jan 01, 2018 | - - |
Retinitis pigmentosa Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 22, 2021 | Variant summary: IFT140 c.2577+25G>A is located at a position not widely known to affect splicing. Several computational tools predict a significant impact on normal splicing: One predict the variant weakens a 5' donor site. Three predict the variant strengthens a cryptic 5' donor site. One predict the variant creates a 5' donor site. Patient RNA analysis confirmed that a novel donor splice site within the intron 20 resulted in the incorporation of 21 additional base pairs (r.2577_2578insGTGAGGGGCGCCCGCCATGGG) that are predicted to add seven new amino acids to the protein sequence (p.Leu859_Glu860insValArgGlyAlaArgHisGly; Geoffroy_2018). The variant was absent in 125168 control chromosomes. c.2577+25G>A has been reported in the literature in two siblings affected with retinitis pigmentosa, short stature, brachydactyly, moderate renal failure and overweight (Geoffroy_2018). In this same study, functional analysis on the patients cells further revealed a reduced level of ciliated cells and mislocalization of the IFT140 mutant away from the cilia base. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
Computational scores
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Name
Calibrated prediction
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DG_spliceai
Position offset: 4
Find out detailed SpliceAI scores and Pangolin per-transcript scores at