Genetic Variant IFITM5:p.Arg34Gly (chr11-299391-G-C) – ACMG Classification: Uncertain_significance (5 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1PM2PP3

The NM_001025295.3(IFITM5):c.100C>G(p.Arg34Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000701 in 1,425,618 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R34Q) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 7.0e-7 ( 0 hom. )

Consequence

IFITM5
NM_001025295.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.40

Publications

1 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 6 benign, 7 uncertain in NM_001025295.3

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.77

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IFITM5	NM_001025295.3 link	c.100C>G	p.Arg34Gly	missense_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 link	c.100C>G	p.Arg34Gly	missense_variant	Exon 1 of 2	1	NM_001025295.3	ENSP00000372059.2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.01e-7

AC:

AN:

1425618

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

706850

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32028

American (AMR)

AF:

0.00

AC:

AN:

39610

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25156

East Asian (EAS)

AF:

0.0000269

AC:

AN:

37162

South Asian (SAS)

AF:

0.00

AC:

AN:

81496

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50184

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5700

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1095324

Other (OTH)

AF:

0.00

AC:

AN:

58958

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Uncertain

0.11

BayesDel_noAF

Uncertain

-0.080

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Pathogenic

0.82

Eigen

Benign

-0.35

Eigen_PC

Benign

-0.56

FATHMM_MKL

Benign

0.45

LIST_S2

Uncertain

0.86

M_CAP

Pathogenic

0.45

MetaRNN

Pathogenic

0.77

MetaSVM

Benign

-0.32

MutationAssessor

Pathogenic

3.0

PhyloP100

1.4

PrimateAI

Uncertain

0.62

PROVEAN

Uncertain

-4.2

REVEL

Uncertain

0.38

Sift

Uncertain

0.017

Sift4G

Uncertain

0.010

Polyphen

0.72

Vest4

0.55

MutPred

0.54

Gain of disorder (P = 0.1584);

MVP

0.72

MPC

0.061

ClinPred

0.98

GERP RS

1.4

PromoterAI

-0.0040

Neutral

(source)

Varity_R

0.43

gMVP

0.48

Mutation Taster

=81/19

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over