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 Pathogenic. The variant received 13 ACMG points: 14P and 1B. PS3 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 (★★). ClinVar reports functional evidence for this variant: "SCV000928325: 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)." and additional evidence is available in ClinVar.

• 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:24
• Conservation: PhyloP100: 0.756
• Publications: 73 publications found

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: G2P, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 13 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000928325: 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).; SCV002767906: 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).; SCV004101347: 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).; SCV005091050: Well-established functional studies show damaging effect on the gene or gene product. PMID:38681748; SCV005416813: "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product."; SCV006584988: "Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product." PMID: 25251575; SCV002028039: 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); PMID: 23674381; SCV005356866: 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).
• 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 VariationId is 37143.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.21). . Strength limited to SUPPORTING due to the PP5.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IFITM5	NM_001025295.3	MANE Select	c.-14C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 2	NP_001020466.1	A6NNB3
	IFITM5	NM_001025295.3	MANE Select	c.-14C>T		5_prime_UTR	Exon 1 of 2	NP_001020466.1	A6NNB3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IFITM5	ENST00000382614.2	TSL:1 MANE Select	c.-14C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 2	ENSP00000372059.2	A6NNB3
	IFITM5	ENST00000382614.2	TSL:1 MANE Select	c.-14C>T		5_prime_UTR	Exon 1 of 2	ENSP00000372059.2	A6NNB3

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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 27496

American (AMR) AF: 0.00 AC: 0 AN: 22656

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19238

East Asian (EAS) AF: 0.00 AC: 0 AN: 32960

South Asian (SAS) AF: 0.00 AC: 0 AN: 65468

European-Finnish (FIN) AF: 0.0000227 AC: 1 AN: 44034

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3912

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1036062

Other (OTH) AF: 0.00 AC: 0 AN: 53824

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
15	-	-	Osteogenesis imperfecta type 5 (15)
5	-	-	not provided (5)
2	-	-	Osteogenesis imperfecta (2)
1	-	-	IFITM5-related disorder (1)
1	-	-	Postmenopausal osteoporosis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.21
CADD	Benign	21
DANN	Benign	0.94
PhyloP100		0.76
PromoterAI		0.061	Neutral
Mutation Taster		=102/198	disease causing (ClinVar)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs587776916;

hg19: chr11-299504;