NM_001025295.3:c.-14C>T
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PM2PP5_Very_StrongBP4
The NM_001025295.3(IFITM5):c.-14C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000766 in 1,305,650 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Consequence
NM_001025295.3 5_prime_UTR_premature_start_codon_gain
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| IFITM5 | NM_001025295.3 | c.-14C>T | 5_prime_UTR_premature_start_codon_gain_variant | Exon 1 of 2 | ENST00000382614.2 | NP_001020466.1 | ||
| IFITM5 | NM_001025295.3 | c.-14C>T | 5_prime_UTR_variant | Exon 1 of 2 | ENST00000382614.2 | NP_001020466.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| IFITM5 | ENST00000382614.2 | c.-14C>T | 5_prime_UTR_premature_start_codon_gain_variant | Exon 1 of 2 | 1 | NM_001025295.3 | ENSP00000372059.2 | |||
| IFITM5 | ENST00000382614.2 | c.-14C>T | 5_prime_UTR_variant | Exon 1 of 2 | 1 | NM_001025295.3 | ENSP00000372059.2 |
Frequencies
GnomAD3 genomes
GnomAD4 exome AF: 7.66e-7 AC: 1AN: 1305650Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0AN XY: 636106
GnomAD4 genome
ClinVar
Submissions by phenotype
Osteogenesis imperfecta type 5 Pathogenic:13
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PM2_Supporting+PS3_Supporting+PS4+PM6_VeryStrong+PP4+PP1_Strong -
The IFITM5 c.-14C>T variant (rs587776916) is reported in the literature as a recurrent variant in individuals affected with osteogenesis imperfecta type V, including several de novo occurrences (Cho 2012, Lazarus 2014, Maddirevula 2018, Rauch 2013, Shapiro 2013, Tyurin 2022, Zhytnik 2019). This variant is also reported in ClinVar (Variation ID: 37143), but is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. This variant is located in the 5' untranslated region and creates a novel protein translation start codon, resulting in the addition of five amino acids (Cho 2012, Lazarus 2014). Based on available information, this variant is considered to be pathogenic. References: Cho TJ et al. A single recurrent mutation in the 5'-UTR of IFITM5 causes osteogenesis imperfecta type V. Am J Hum Genet. 2012 Aug 10;91(2):343-8. PMID: 22863190. Lazarus S et al. The IFITM5 mutation c.-14C > T results in an elongated transcript expressed in human bone; and causes varying phenotypic severity of osteogenesis imperfecta type V. BMC Musculoskelet Disord. 2014 Mar 27;15:107. PMID: 24674092. Maddirevula S et al. Expanding the phenome and variome of skeletal dysplasia. Genet Med. 2018 Dec;20(12):1609-1616. PMID: 29620724. Rauch F et al. Osteogenesis imperfecta type V: marked phenotypic variability despite the presence of the IFITM5 c.-14C>T mutation in all patients. J Med Genet. 2013 Jan;50(1):21-4. PMID: 23240094. Shapiro JR et al. Phenotypic variability of osteogenesis imperfecta type V caused by an IFITM5 mutation. J Bone Miner Res. 2013 Jul;28(7):1523-30. PMID: 23408678. Tyurin A et al. Does the c.-14C>T Mutation in the IFITM5 Gene Provide Identical Phenotypes for Osteogenesis Imperfecta Type V? Data from Russia and a Literature Review. Biomedicines. 2022 Sep 22;10(10):2363. PMID: 36289625. Zhytnik L et al. IFITM5 pathogenic variant causes osteogenesis imperfecta V with various phenotype severity in Ukrainian and Vietnamese patients. Hum Genomics. 2019 Jun 3;13(1):25. PMID: 31159867. -
PS3, PS4, PM2, PP5 - Well-established functional studies show damaging effect on the gene or gene product. Low frequency in gnomAD population databases. This variant has been previously reported as causative for Osteogenesis imperfecta. (PMID:38681748). -
Heterozygous variant c.-14C>T in 5' UTR has been observed in IFITM5 gene. The proband born of a non-consanguineous marriage, presented with clinical indications of inability to stand or walk, traumatic fracture in midshaft of the right femur and had soft skull at birth. X-ray showed multiple rib fractures. The patient in our clinical analysis was diagnosed with the said variant in an autosomal dominant mode of inheritance. This variant introduces alternative start codon, adding 5 amino acid residues to the N terminus of the protein. Transgenic mice models show that mutant IFITM5 mice exhibit perinatal lethality with severe defects of the long bones and ribs (Lietman CD et al. Journal of Bone and Mineral Research 2015). The variant has not been reported in the 1000 genomes and ExAC databases and has a minor allele frequency of 0.02%. The in silico prediction of the variant is possibly damaging by MutationTaster2. In summary, the said variant meets our criteria to be classified as pathogenic based on the mode of inheritance, in silico prediction and allele frequency in population databases. -
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The IFITM5 c.-14C>T variant occurs in the 5' untranslated region. Across a selection of the available literature, this variant has been identified in over 95 individuals with variable phenotypes consistent with osteogenesis imperfecta, type V (PMID: 22863190; 23240094; 23408678; 23612438; 23674381; 23813632; 24674092; 31159867; 31244780). Both familial segregation as well as de novo occurrences have been observed. This variant is predicted to introduce five amino acid residues at the N-terminus of the IFITM5 protein due to the creation of an in-frame translation initiation codon upstream of the wild-type initiation codon. In vitro expression of this variant in a cell line confirmed this prediction due to the presence of a slightly larger protein detected by immunoblotting (PMID: 22863190). Additionally, transgenic mice that express this variant exhibited bone abnormalities consistent with those observed in patients (PMID: 25251575). This variant has been classified as pathogenic by at least three submitters in ClinVar. This variant is not observed in version 2.1.1 or version 3.1.2 of the Genome Aggregation Database. Based on the available evidence, the c.-14C>T variant is classified as pathogenic for osteogenesis imperfecta, type V. -
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ACMG classification criteria: PS3 supporting, PS4, PM2, PM6 strong, PP1 -
Variant summary: IFITM5 c.-14C>T is located in the untranslated mRNA region upstream of the initiation codon. It has been found to generate an upstream start codon which results in an IFITM5 protein with five additional amino acids at its N-terminus (Cho_2012). The variant was absent in 72430 control chromosomes (gnomAD). c.-14C>T has been reported in the literature in the heterozygous state in multiple individuals affected with Osteogenesis Imperfecta Type 5, has been found to segregate with the disease phenotype in multiple families, and has been reported as a de novo occurrence in several affected individuals (e.g. Cho_2012, Liu_2017). 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: 22863190, 28725987). Fourteen submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic (n=13)/likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic. -
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Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0101 - Neomorphic gain of function is the proposed mechanism of disease in this gene and is associated with osteogenesis imperfecta, type V (MIM# 610967) (PMID: 35216266). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0217 - Non-coding variant shown to affect the translated protein. This variant introduces an alternative in-frame translation start site upstream, resulting in 5 additional amino acids at the N-terminus (PMIDs: 22863190, 22863195). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in more than 15 unrelated patients with osteogenesis imperfecta type V (ClinVar; PMIDs: 22863190, 22863195, 31159867). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Knockin mice embryos with this variant revealed skeletal anomalies (PMID: 29174564). In addition, when overexpressed in MC3T3-E1 and MLO-A5 cells, this variant activated the reporters dependent on MEF2, NFATc, and NR4A significantly compared to wild type (PMID: 35216266). (SP) 1204 - This variant has been shown to be de novo in the proband (parental status not tested but assumed) (by segregation analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
not provided Pathogenic:5
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This variant occurs in a non-coding region of the IFITM5 gene. It does not change the encoded amino acid sequence of the IFITM5 protein. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with osteogenesis imperfecta (PMID: 22863190, 23977282, 31099171). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 37143). For these reasons, this variant has been classified as Pathogenic. -
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Published functional studies in mice demonstrate that c.-14 C>T results in severe skeletal defects caused by alterations to protein interactions and signaling cascades that affect differentiation and mineralization of bone (Lietman et al., 2015); Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 23674381, 31715670, 24674092, 23612438, 23408678, 23240094, 23977282, 27678411, 27029692, 25251575, 22863190, 22863195, 24478195, 29499418, 29188603, 29620724, 31159867, 31244780, 31099171, 32552793, 32770541, 33470886, 33935965, 32123938, 33939306, 33726816, 33360005) -
Osteogenesis imperfecta Pathogenic:2
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IFITM5-related disorder Pathogenic:1
The IFITM5 c.-14C>T variant is located in the 5' untranslated region. This variant is in the 5’ untranslated region (5’UTR) of the gene and is a known recurrent pathogenic variant in patients with osteogenesis imperfecta (Cho et al. 2012. PubMed ID: 22863190; Lazarus et al. 2014. PubMed ID: 24674092; Mrosk et al. 2018. PubMed ID: 29499418). Functional studies have shown that this variant introduces a novel in frame start codon in the 5’UTR of the gene and results in a longer protein (Lazarus et al. 2014. PubMed ID: 24674092). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic. -
Postmenopausal osteoporosis Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at