rs587776916

Variant names:

• chr11-299504-G-A
• rs587776916
• NM_001025295.3:c.-14C>T

Your query was ambiguous. Multiple possible variants found:

• chr11-299504-G-A
• chr11-299504-G-C
• chr11-299504-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PM2 PP5_Very_Strong BP4

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:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.7e-7 (0 hom.)
• Consequence: IFITM5 NM_001025295.3 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:22
• Conservation: PhyloP100: 0.756

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-299504-G-A is Pathogenic according to our data. Variant chr11-299504-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 37143.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-299504-G-A is described in Lovd as [Pathogenic]. Variant chr11-299504-G-A is described in Lovd as [Pathogenic]. Variant chr11-299504-G-A is described in Lovd as [Likely_pathogenic].
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.21). . Strength limited to SUPPORTING due to the PP5.

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 Cov.: 33

GnomAD4 exome AF: 7.66e-7 AC: 1 AN: 1305650 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 636106

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000227

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:22

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Osteogenesis imperfecta type 5 Pathogenic:13

Mar 01, 2015

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

-

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2_Supporting+PS3_Supporting+PS4+PM6_VeryStrong+PP4+PP1_Strong -

Sep 25, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Dec 01, 2023

Laboratory of Medical Genetics, National & Kapodistrian University of Athens

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). -

Jun 19, 2019

Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

-

Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 28, 2019

Mendelics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 30, 2023

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jun 18, 2018

Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 20, 2021

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG classification criteria: PS3 supporting, PS4, PM2, PM6 strong, PP1 -

Jun 02, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Apr 06, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 17, 2023

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Nov 30, 2019

Blueprint Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 26, 2017

Clinical Genetics and Genomics, Karolinska University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 06, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Mar 01, 2021

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 17, 2021

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Sep 07, 2021

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 21, 2023

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

IFITM5-related disorder Pathogenic:1

Sep 02, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Jun 14, 2021

Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.21
CADD	Benign	21
DANN	Benign	0.94

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs587776916; hg19: chr11-299504;