chr11-299372-G-A

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM2PM5PP3_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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S40W) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

IFITM5
NM_001025295.3 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 8.20

Publications

35 publications found

Variant links:

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]

IFITM5 Gene-Disease associations (from GenCC):

osteogenesis imperfecta type 5
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Orphanet

IFITM5 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 16 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr11-299372-G-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 689498.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 VariationId is 183677.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001025295.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IFITM5	NM_001025295.3	MANE Select	c.119C>T	p.Ser40Leu	missense	Exon 1 of 2	NP_001020466.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IFITM5	ENST00000382614.2	TSL:1 MANE Select	c.119C>T	p.Ser40Leu	missense	Exon 1 of 2	ENSP00000372059.2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1443964

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

717030

African (AFR)

AF:

0.00

AC:

AN:

32702

American (AMR)

AF:

0.00

AC:

AN:

42694

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25684

East Asian (EAS)

AF:

0.00

AC:

AN:

38394

South Asian (SAS)

AF:

0.00

AC:

AN:

83580

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51440

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5734

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1104104

Other (OTH)

AF:

0.00

AC:

AN:

59632

GnomAD4 genome

Cov.:

Alfa

AF:

0.00167

Hom.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Osteogenesis imperfecta type 5

Pathogenic:5

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:research

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.

Oct 31, 2024

3billion

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The variant is not observed in the gnomAD v4.1.0 dataset. Predicted Consequence/Location: Missense variant. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.96 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.12 (>=0.6, sensitivity 0.72 and precision 0.9)]. The same nucleotide change resulting in the same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000183677 /PMID: 24478195). A different missense change at the same codon (p.Ser40Trp) has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000689498 /PMID: 30985308). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

Jun 01, 2014

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

Sep 04, 2024

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.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.

Sep 10, 2024

Clinical Genetics and Genomics, Karolinska University Hospital

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.(Ser40Leu) variant in the IFITM5 gene was seen de novo in a fetus with OI type 5.

not provided

Pathogenic:2

Oct 13, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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.

Dec 29, 2021

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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)

IFITM5-related disorder

Pathogenic:1

Mar 14, 2024

PreventionGenetics, part of Exact Sciences

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

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: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.88

BayesDel_addAF

Pathogenic

0.50

BayesDel_noAF

Pathogenic

0.47

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.90

Eigen

Uncertain

0.61

Eigen_PC

Uncertain

0.46

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

M_CAP

Pathogenic

0.73

MetaRNN

Pathogenic

0.98

MetaSVM

Pathogenic

0.96

MutationAssessor

Pathogenic

3.7

PhyloP100

8.2

PrimateAI

Pathogenic

0.80

PROVEAN

Pathogenic

-5.8

REVEL

Pathogenic

0.96

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0030

Polyphen

1.0

Vest4

0.89

MutPred

0.82

Loss of catalytic residue at S40 (P = 0.0077)

MVP

0.83

MPC

0.082

ClinPred

1.0

GERP RS

4.2

PromoterAI

-0.0017

Neutral

(source)

Varity_R

0.96

gMVP

0.92

Mutation Taster

=10/90

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.14

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over