rs138004478
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PS1PM2PP5
The NM_020800.3(IFT80):c.721G>C(p.Gly241Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000731 in 1,614,156 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Pathogenicin ClinVar.
Frequency
Consequence
NM_020800.3 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
IFT80 | NM_020800.3 | c.721G>C | p.Gly241Arg | missense_variant | 8/20 | ENST00000326448.12 | |
TRIM59-IFT80 | NR_148401.1 | n.1429G>C | non_coding_transcript_exon_variant | 6/19 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
IFT80 | ENST00000326448.12 | c.721G>C | p.Gly241Arg | missense_variant | 8/20 | 1 | NM_020800.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000401 AC: 61AN: 152218Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000676 AC: 17AN: 251404Hom.: 0 AF XY: 0.0000589 AC XY: 8AN XY: 135866
GnomAD4 exome AF: 0.0000390 AC: 57AN: 1461820Hom.: 0 Cov.: 31 AF XY: 0.0000344 AC XY: 25AN XY: 727228
GnomAD4 genome ? AF: 0.000400 AC: 61AN: 152336Hom.: 0 Cov.: 32 AF XY: 0.000295 AC XY: 22AN XY: 74492
ClinVar
Submissions by phenotype
Jeune thoracic dystrophy Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 11, 2023 | This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 241 of the IFT80 protein (p.Gly241Arg). This variant is present in population databases (rs138004478, gnomAD 0.1%). This missense change has been observed in individuals with short-rib thoracic dysplasia (PMID: 19648123, 29068549, 30266093). ClinVar contains an entry for this variant (Variation ID: 406218). 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 expected to disrupt IFT80 protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. - |
Likely pathogenic, no assertion criteria provided | research | University of Washington Center for Mendelian Genomics, University of Washington | - | - - |
Pathogenic, no assertion criteria provided | research | Dan Cohn Lab, University Of California Los Angeles | Jun 01, 2017 | - - |
Short-rib thoracic dysplasia 6 with or without polydactyly Pathogenic:2
Likely pathogenic, no assertion criteria provided | research | University of Washington Center for Mendelian Genomics, University of Washington | - | - - |
Pathogenic, no assertion criteria provided | research | Dan Cohn Lab, University Of California Los Angeles | Jun 01, 2017 | - - |
Asphyxiating thoracic dystrophy 2 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Jun 01, 2023 | The IFT80 c.721G>C; p.Gly241Arg variant (rs138004478) is reported in the literature in the homozygous or compound heterozygous state in individuals affected with short-rib thoracic dysplasia II, asphyxiating thoracic dystrophy, or Jeune-Verma-Naumoff dysplasia (Cavalcanti 2011, Normand 2018, Zhang 2018). This variant is also reported in ClinVar (Variation ID: 406218), and is found in the African/African-American population with an allele frequency of 0.12% (30/24974 alleles) in the Genome Aggregation Database. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.628). Based on available information, this variant is considered to be likely pathogenic. References: Cavalcanti D et al. Mutation in IFT80 in a fetus with the phenotype of Verma-Naumoff provides molecular evidence for Jeune-Verma-Naumoff dysplasia spectrum. J Med Genet. 2011; 48(2):88-92. PMID: 19648123. Normand EA et al. Clinical exome sequencing for fetuses with ultrasound abnormalities and a suspected Mendelian disorder. Genome Med. 2018 Sep 28;10(1):74. PMID: 30266093. Zhang W et al. Expanding the genetic architecture and phenotypic spectrum in the skeletal ciliopathies. Hum Mutat. 2018 Jan;39(1):152-166. PMID: 29068549. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Mar 02, 2017 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at