chr16-1587961-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.874G>A(p.Val292Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000411 in 1,460,968 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000041 ( 0 hom. )
Consequence
IFT140
NM_014714.4 missense
NM_014714.4 missense
Scores
2
12
5
Clinical Significance
Conservation
PhyloP100: 2.55
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
MetaRNN computational evidence supports a deleterious effect, 0.858
PP5
Variant 16-1587961-C-T is Pathogenic according to our data. Variant chr16-1587961-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 97053.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-1587961-C-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
IFT140 | NM_014714.4 | c.874G>A | p.Val292Met | missense_variant | 8/31 | ENST00000426508.7 | |
LOC105371046 | NR_135176.1 | n.59+7376C>T | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
IFT140 | ENST00000426508.7 | c.874G>A | p.Val292Met | missense_variant | 8/31 | 5 | NM_014714.4 | P1 | |
ENST00000563162.1 | n.59+7376C>T | intron_variant, non_coding_transcript_variant | 2 | ||||||
IFT140 | ENST00000439987.6 | n.935G>A | non_coding_transcript_exon_variant | 7/19 | 2 | ||||
IFT140 | ENST00000397417.6 | c.329-3541G>A | intron_variant, NMD_transcript_variant | 5 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
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32
GnomAD3 exomes AF: 0.00000401 AC: 1AN: 249478Hom.: 0 AF XY: 0.00000741 AC XY: 1AN XY: 134878
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GnomAD4 exome AF: 0.00000411 AC: 6AN: 1460968Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2AN XY: 726648
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GnomAD4 genome Cov.: 32
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Jeune thoracic dystrophy Pathogenic:2
Pathogenic, no assertion criteria provided | research | Dan Cohn Lab, University Of California Los Angeles | Jun 01, 2017 | - - |
Likely pathogenic, no assertion criteria provided | research | University of Washington Center for Mendelian Genomics, University of Washington | - | - - |
Saldino-Mainzer syndrome;C4518774:Joubert syndrome with Jeune asphyxiating thoracic dystrophy Pathogenic:1
Pathogenic, criteria provided, single submitter | research | Laboratory of Medical Genetics (UMR_S 1112), INSERM/Strasbourg University | Jan 01, 2018 | - - |
Saldino-Mainzer syndrome Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | May 01, 2013 | - - |
Retinitis pigmentosa Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 29, 2024 | Variant summary: IFT140 c.874G>A (p.Val292Met) results in a conservative amino acid change located in the WD40/YVTN repeat-like-containing domain superfamily (IPR015943) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 249478 control chromosomes (gnomAD). c.874G>A has been reported in the literature in multiple individuals affected with IFT140 related disorders (examples: Perrault_2012, Schmidts_2013, Dineiro_2020). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 32483926, 22503633, 23418020). ClinVar contains an entry for this variant (Variation ID: 97053). Based on the evidence outlined above, the variant was classified as pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Uncertain
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D
M_CAP
Benign
D
MetaRNN
Pathogenic
D
MetaSVM
Uncertain
T
MutationAssessor
Uncertain
M
MutationTaster
Benign
D
PrimateAI
Uncertain
T
PROVEAN
Benign
N
REVEL
Uncertain
Sift
Benign
D
Sift4G
Uncertain
D
Polyphen
D
Vest4
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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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