NM_001025295.3:c.-14C>T

Variant names:

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

Variant summary

Our verdict is Likely pathogenic. The variant received 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:24
• Conservation: PhyloP100: 0.756
• Publications: 71 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, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_pathogenic. The variant received 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 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

Other links and lift over

dbSNP: rs587776916; hg19: chr11-299504;