rs551515830
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Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1PM2PP3
The NM_025103.4(IFT74):c.120+2dup variant causes a splice donor change. The variant allele was found at a frequency of 0.000763 in 1,613,954 control chromosomes in the GnomAD database, including 1 homozygotes. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.00045 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00080 ( 1 hom. )
Consequence
IFT74
NM_025103.4 splice_donor
NM_025103.4 splice_donor
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 3.99
Genes affected
IFT74 (HGNC:21424): (intraflagellar transport 74) This gene encodes a core intraflagellar transport (IFT) protein which belongs to a multi-protein complex involved in the transport of ciliary proteins along axonemal microtubules. IFT proteins are found at the base of the cilium as well as inside the cilium, where they assemble into long arrays between the ciliary base and tip. This protein, together with intraflagellar transport protein 81, binds and transports tubulin within cilia and is required for ciliogenesis. Naturally occurring mutations in this gene are associated with amyotrophic lateral sclerosis--frontotemporal dementia and Bardet-Biedl Syndrome. [provided by RefSeq, Mar 2017]
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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 6, offset of 40, new splice context is: aagGTggga. 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;
PP3
?
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
IFT74 | NM_025103.4 | c.120+2dup | splice_donor_variant | ENST00000380062.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
IFT74 | ENST00000380062.10 | c.120+2dup | splice_donor_variant | 1 | NM_025103.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000447 AC: 68AN: 152206Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000325 AC: 81AN: 249506Hom.: 0 AF XY: 0.000295 AC XY: 40AN XY: 135374
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GnomAD4 exome AF: 0.000796 AC: 1163AN: 1461748Hom.: 1 Cov.: 31 AF XY: 0.000756 AC XY: 550AN XY: 727174
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GnomAD4 genome ? AF: 0.000447 AC: 68AN: 152206Hom.: 0 Cov.: 32 AF XY: 0.000336 AC XY: 25AN XY: 74362
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ClinVar
Significance: Uncertain significance
Submissions summary: Pathogenic:1Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Short-rib thoracic dysplasia 6 with or without polydactyly Pathogenic:1Uncertain:1
Likely pathogenic, no assertion criteria provided | research | University of Washington Center for Mendelian Genomics, University of Washington | - | - - |
Uncertain significance, no assertion criteria provided | research | Dan Cohn Lab, University Of California Los Angeles | Jun 01, 2017 | - - |
IFT74-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Feb 21, 2024 | The IFT74 c.120+2dupT variant is predicted to result in an intronic duplication. This variant is predicted to impact the consensus donor site based on available splicing prediction programs (Alamut Visual Plus v1.6.1), although it does not eliminate the consensus GT donor site sequence at the junction of exon 2 and intron 2 (GT>GTT). This variant has been identified in the heterozygous state in one patient with an autosomal recessive skeletal ciliopathy known as short rib-polydactyly syndrome type II (Table S3, Zhang et al. 2018. PubMed ID: 29068549). This variant is reported in 0.066% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 05, 2022 | This sequence change falls in intron 2 of the IFT74 gene. It does not directly change the encoded amino acid sequence of the IFT74 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs551515830, gnomAD 0.07%). This variant has been observed in individual(s) with clinical features of IFT74-related conditions (PMID: 29068549). ClinVar contains an entry for this variant (Variation ID: 446698). 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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DS_DL_spliceai
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at