11-298565-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001025295.3(IFITM5):c.335C>G(p.Ala112Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: IFITM5 NM_001025295.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 6.03

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16501528).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IFITM5	NM_001025295.3	c.335C>G	p.Ala112Gly	missense_variant	2/2	ENST00000382614.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IFITM5	ENST00000382614.2	c.335C>G	p.Ala112Gly	missense_variant	2/2	1	NM_001025295.3	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jul 31, 2023	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. 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 tolerated. ClinVar contains an entry for this variant (Variation ID: 387521). This variant has not been reported in the literature in individuals affected with IFITM5-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 112 of the IFITM5 protein (p.Ala112Gly). -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 30, 2016	The A112G variant in the IFITM5 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The A112G variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The A112G variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is not conserved across species. In silico analysis predicts this variant likely does not alter the protein structure/function. We interpret A112G as a variant of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.085	T
BayesDel_noAF	Benign	-0.36
Cadd	Uncertain	24
Dann	Uncertain	0.99
DEOGEN2	Benign	0.033	T
Eigen	Benign	-0.16
Eigen_PC	Benign	0.066
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.73	T
M_CAP	Benign	0.063	D
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	0.0	N
MutationTaster	Benign	0.99	N
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.24
Sift	Benign	0.23	T
Sift4G	Benign	0.38	T
Polyphen		0.0080	B
Vest4		0.10
MutPred		0.35		Loss of stability (P = 0.077);
MVP		0.64
MPC		0.012
ClinPred		0.78	D
GERP RS		4.9
Varity_R		0.17
gMVP		0.55

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: rs139459814; hg19: chr11-298565;