12-6548814-C-T

Variant summary

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

The NM_001193457.2(IFFO1):​c.1116G>A​(p.Met372Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000149 in 1,612,896 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000015 ( 0 hom. )

Consequence

IFFO1
NM_001193457.2 missense

Scores

2
17

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.497
Variant links:
Genes affected
IFFO1 (HGNC:24970): (intermediate filament family orphan 1) This gene is a member of the intermediate filament family. Intermediate filaments are proteins which are primordial components of the cytoskeleton and nuclear envelope. The proteins encoded by the members of this gene family are evolutionarily and structurally related but have limited sequence homology, with the exception of the central rod domain. Multiple alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2010]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
IFFO1NM_001193457.2 linkc.1116G>A p.Met372Ile missense_variant Exon 6 of 10 ENST00000619571.5 NP_001180386.1 A0A087WZ16Q9Y4M3B4DQQ1Q6P593

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
IFFO1ENST00000619571.5 linkc.1116G>A p.Met372Ile missense_variant Exon 6 of 10 2 NM_001193457.2 ENSP00000482285.1 A0A087WZ16

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152146
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000655
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000124
AC:
3
AN:
242382
Hom.:
0
AF XY:
0.0000228
AC XY:
3
AN XY:
131694
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000110
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.000169
GnomAD4 exome
AF:
0.0000151
AC:
22
AN:
1460750
Hom.:
0
Cov.:
33
AF XY:
0.0000206
AC XY:
15
AN XY:
726584
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.000303
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000900
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152146
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74316
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.0000655
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000378
ExAC
AF:
0.00000824
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Mar 07, 2025
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.1116G>A (p.M372I) alteration is located in exon 6 (coding exon 6) of the IFFO1 gene. This alteration results from a G to A substitution at nucleotide position 1116, causing the methionine (M) at amino acid position 372 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.21
BayesDel_addAF
Benign
-0.15
T
BayesDel_noAF
Benign
-0.23
CADD
Uncertain
25
DANN
Benign
0.97
DEOGEN2
Benign
0.0046
.;T;.;T;.;.;.
Eigen
Benign
0.064
Eigen_PC
Benign
0.16
FATHMM_MKL
Benign
0.71
D
LIST_S2
Uncertain
0.90
.;D;D;D;D;D;D
M_CAP
Benign
0.046
D
MetaRNN
Benign
0.28
T;T;T;T;T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
1.0
.;.;.;L;.;.;.
PrimateAI
Uncertain
0.55
T
PROVEAN
Benign
-0.22
N;N;N;N;.;N;.
REVEL
Benign
0.18
Sift
Benign
0.10
T;T;T;T;.;T;.
Sift4G
Benign
0.30
T;T;T;T;T;T;T
Polyphen
0.0020
.;.;B;B;.;B;.
Vest4
0.44
MutPred
0.60
.;.;.;Loss of disorder (P = 0.0756);.;.;.;
MVP
0.81
MPC
0.65
ClinPred
0.20
T
GERP RS
4.6
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.20
gMVP
0.38

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.46
Details are displayed if max score is > 0.2
DS_AG_spliceai
0.46
Position offset: -2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs373663883; hg19: chr12-6657980; API