rs431905522
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_014714.4(IFT140):c.1380del(p.Asn460LysfsTer28) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. N460N) has been classified as Uncertain significance. Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Consequence
IFT140
NM_014714.4 frameshift
NM_014714.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 0.216
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 18 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 16-1583365-CG-C is Pathogenic according to our data. Variant chr16-1583365-CG-C is described in ClinVar as [Pathogenic]. Clinvar id is 97055.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.1380del | p.Asn460LysfsTer28 | frameshift_variant | 12/31 | ENST00000426508.7 | |
LOC105371046 | NR_135176.1 | n.59+2781del | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
IFT140 | ENST00000426508.7 | c.1380del | p.Asn460LysfsTer28 | frameshift_variant | 12/31 | 5 | NM_014714.4 | P1 | |
ENST00000563162.1 | n.59+2781del | intron_variant, non_coding_transcript_variant | 2 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251220Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135800
GnomAD3 exomes
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GnomAD4 exome Cov.: 31
GnomAD4 exome
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31
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
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32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Short-rib thoracic dysplasia without polydactyly Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | May 01, 2013 | - - |
Saldino-Mainzer syndrome;C4540439:Retinitis pigmentosa 80 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | May 17, 2022 | - - |
Saldino-Mainzer syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Feb 09, 2022 | This sequence change creates a premature translational stop signal (p.Asn460Lysfs*28) in the IFT140 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in IFT140 are known to be pathogenic (PMID: 22503633, 23418020, 24009529, 26216056). This variant is present in population databases (rs431905522, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with asphyxiating thoracic dystrophy (PMID: 23418020). ClinVar contains an entry for this variant (Variation ID: 97055). For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at