rs1403669200
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong
The NM_014714.4(IFT140):c.454C>T(p.Leu152Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000031 in 1,614,122 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L152V) has been classified as Uncertain significance.
Frequency
Consequence
NM_014714.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
IFT140 | NM_014714.4 | c.454C>T | p.Leu152Phe | missense_variant | 5/31 | ENST00000426508.7 | |
LOC105371046 | NR_135176.1 | n.60-11911G>A | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
IFT140 | ENST00000426508.7 | c.454C>T | p.Leu152Phe | missense_variant | 5/31 | 5 | NM_014714.4 | P1 | |
ENST00000563162.1 | n.60-11911G>A | intron_variant, non_coding_transcript_variant | 2 | ||||||
IFT140 | ENST00000439987.6 | n.515C>T | non_coding_transcript_exon_variant | 4/19 | 2 | ||||
IFT140 | ENST00000397417.6 | c.329-8084C>T | intron_variant, NMD_transcript_variant | 5 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152242Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251382Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135886
GnomAD4 exome AF: 0.00000274 AC: 4AN: 1461880Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3AN XY: 727240
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152242Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74378
ClinVar
Submissions by phenotype
Saldino-Mainzer syndrome Pathogenic:2
Pathogenic, criteria provided, single submitter | research | Laboratory of Medical Genetics (UMR_S 1112), INSERM/Strasbourg University | Jan 01, 2018 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 21, 2023 | This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 152 of the IFT140 protein (p.Leu152Phe). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This missense change has been observed in individual(s) with clinical features of asphyxiating thoracic dystrophy and/or Mainzer-Saldino syndrome (PMID: 23418020, 29688594; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 523179). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt IFT140 protein function with a negative predictive value of 95%. 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at