Genetic Variant IFFO2:p.Lys478Arg (chr1-18910357-T-C) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_001136265.2(IFFO2):c.1433A>G(p.Lys478Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,458 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

IFFO2
NM_001136265.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.54

Variant links:

Genes affected

IFFO2 (HGNC:27006): (intermediate filament family orphan 2) Predicted to be located in intermediate filament. [provided by Alliance of Genome Resources, Apr 2022]

IFFO2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.292711).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IFFO2	NM_001136265.2 link	c.1433A>G	p.Lys478Arg	missense_variant	Exon 8 of 9	ENST00000455833.7	NP_001129737.1	Q5TF58
IFFO2	XM_011540630.3 link	c.1292A>G	p.Lys431Arg	missense_variant	Exon 7 of 8		XP_011538932.1
IFFO2	XM_047444839.1 link	c.1196A>G	p.Lys399Arg	missense_variant	Exon 6 of 7		XP_047300795.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
IFFO2	ENST00000455833.7 link	c.1433A>G	p.Lys478Arg	missense_variant	Exon 8 of 9	5	NM_001136265.2	ENSP00000387941.2	Q5TF58
IFFO2	ENST00000416166.1 link	c.656A>G	p.Lys219Arg	missense_variant	Exon 7 of 8	3		ENSP00000394655.1	H0Y4W3
IFFO2	ENST00000355609.8 link	c.146A>G	p.Lys49Arg	missense_variant	Exon 2 of 3	5		ENSP00000347820.4	J3KNZ4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000406

AC:

AN:

246542

Hom.:

AF XY:

0.00

AC XY:

AN XY:

133290

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000333

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1459458

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

725712

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000117

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 05, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1433A>G (p.K478R) alteration is located in exon 8 (coding exon 8) of the IFFO2 gene. This alteration results from a A to G substitution at nucleotide position 1433, causing the lysine (K) at amino acid position 478 to be replaced by an arginine (R). 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

0.11

BayesDel_addAF

Benign

-0.0013

BayesDel_noAF

Benign

-0.14

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.29

T;.

Eigen

Benign

0.17

Eigen_PC

Benign

0.19

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.83

T;T

M_CAP

Uncertain

0.12

MetaRNN

Benign

0.29

T;T

MetaSVM

Uncertain

0.15

MutationAssessor

Benign

1.5

L;.

PrimateAI

Uncertain

0.62

PROVEAN

Benign

-0.97

N;N

REVEL

Benign

0.13

Sift

Uncertain

0.020

D;T

Sift4G

Benign

0.084

T;T

Polyphen

0.91

P;.

Vest4

0.28

MutPred

0.37

Loss of methylation at K478 (P = 0.0096);.;

MVP

0.82

MPC

1.8

ClinPred

0.63

GERP RS

3.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.14

gMVP

0.47

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

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

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over