rs786201032
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong
The NM_001025295.3(IFITM5):c.119C>T(p.Ser40Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Genomes: not found (cov: 31)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
IFITM5
NM_001025295.3 missense
NM_001025295.3 missense
Scores
13
5
1
Clinical Significance
Conservation
PhyloP100: 8.20
Genes affected
IFITM5 (HGNC:16644): (interferon induced transmembrane protein 5) This gene encodes a membrane protein thought to play a role in bone mineralization. This gene is located on chromosome 11 in a cluster of related genes which are induced by interferon, however, this gene has not been shown to be interferon inducible. A similar gene, located in a gene cluster on mouse chromosome 7, is a member of the interferon-inducible fragilis gene family. The mouse gene encodes a transmembrane protein described as participating in germ cell competence. A mutation in the 5' UTR of this gene has been associated with osteogenesis imperfecta type V (PMID: 22863190, 22863195). [provided by RefSeq, Aug 2012]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 14 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.981
PP5
Variant 11-299372-G-A is Pathogenic according to our data. Variant chr11-299372-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 183677.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-299372-G-A is described in Lovd as [Pathogenic]. Variant chr11-299372-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
31
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1443964Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 717030
GnomAD4 exome
Data not reliable, filtered out with message: AC0
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0
AN:
1443964
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Cov.:
33
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0
AN XY:
717030
Gnomad4 AFR exome
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GnomAD4 genome
GnomAD4 genome
Cov.:
31
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Osteogenesis imperfecta type 5 Pathogenic:4
| Pathogenic, criteria provided, single submitter | research | Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India | - | A known missense variant, c.119C>T in exon 1 of IFITM5 was observed in a heterozygous state in the proband (Farber et al., 2014). Sanger validation and segregation analysis showed that the variant was present in heterozygous state in the proband and absent in her parents. The variant is absent in gnomAD (v4.1.0) and our in-house database of 3419 exomes. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Sep 04, 2024 | Variant summary: IFITM5 c.119C>T (p.Ser40Leu) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 217238 control chromosomes. c.119C>T has been reported in the literature, arising de novo in at-least two individuals affected with Osteogenesis Imperfecta (example, Chandler_2018, Yap_2024). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 29595812, 37799085). ClinVar contains an entry for this variant (Variation ID: 183677). Based on the evidence outlined above, the variant was classified as pathogenic. - |
| Pathogenic, no assertion criteria provided | literature only | OMIM | Jun 01, 2014 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics and Genomics, Karolinska University Hospital | Sep 10, 2024 | The p.(Ser40Leu) variant in the IFITM5 gene was seen de novo in a fetus with OI type 5. - |
not provided Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Dec 29, 2021 | Not observed in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 24293101, 28232077, 24519609, 24478195, 30039845, 28880886, 28548288, 27914223, 27678411, 27579219, 25387264, 30289614, 24715519, 29595812, 28319678, 31994750, 33942288, 33726816) - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Oct 13, 2023 | This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 40 of the IFITM5 protein (p.Ser40Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with osteogenesis imperfecta (PMID: 24478195, 24519609, 29595812). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 183677). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. For these reasons, this variant has been classified as Pathogenic. - |
IFITM5-related disorder Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Mar 14, 2024 | The IFITM5 c.119C>T variant is predicted to result in the amino acid substitution p.Ser40Leu. This variant is a known pathogenic variant that has been reported as de novo in multiple individuals with osteogenesis imperfecta (Guillén-Navarro et al. 2014. PubMed ID: 24478195; Hoyer-Kuhn et al. 2014. PubMed ID: 24293101; Farber et al. 2014. PubMed ID: 24519609; Rodriguez Celin et al. 2018. PubMed ID: 30039845; Han et al. 2020. PubMed ID: 31994750) and is classified as pathogenic in ClinVar. This variant has not been reported in a large population database, indicating this variant is rare. We interpret this variant to be pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Pathogenic
D
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
H
PrimateAI
Pathogenic
T
PROVEAN
Pathogenic
D
REVEL
Pathogenic
Sift
Uncertain
D
Sift4G
Uncertain
D
Polyphen
D
Vest4
MutPred
Loss of catalytic residue at S40 (P = 0.0077);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at