Genetic Variant IFFO2:p.Arg346Trp (chr1-18916970-G-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_001136265.2(IFFO2):c.1036C>T(p.Arg346Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000786 in 1,399,810 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000079 ( 0 hom. )

Consequence

IFFO2
NM_001136265.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.601

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 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
IFFO2	NM_001136265.2 link	c.1036C>T	p.Arg346Trp	missense_variant	Exon 5 of 9	ENST00000455833.7	NP_001129737.1	Q5TF58
IFFO2	XM_011540630.3 link	c.895C>T	p.Arg299Trp	missense_variant	Exon 4 of 8		XP_011538932.1
IFFO2	XM_047444839.1 link	c.799C>T	p.Arg267Trp	missense_variant	Exon 3 of 7		XP_047300795.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IFFO2	ENST00000455833.7 link	c.1036C>T	p.Arg346Trp	missense_variant	Exon 5 of 9	5	NM_001136265.2	ENSP00000387941.2		Q5TF58
IFFO2	ENST00000416166.1 link	c.259C>T	p.Arg87Trp	missense_variant	Exon 4 of 8	3		ENSP00000394655.1		H0Y4W3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000190

AC:

AN:

158000

Hom.:

AF XY:

0.0000360

AC XY:

AN XY:

83404

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000405

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000163

Gnomad OTH exome

AF:

0.000223

GnomAD4 exome

AF:

0.00000786

AC:

AN:

1399810

Hom.:

Cov.:

AF XY:

0.00000435

AC XY:

AN XY:

690396

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000280

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000126

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000834

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000312

Hom.:

Bravo

AF:

0.0000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 09, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1036C>T (p.R346W) alteration is located in exon 5 (coding exon 5) of the IFFO2 gene. This alteration results from a C to T substitution at nucleotide position 1036, causing the arginine (R) at amino acid position 346 to be replaced by a tryptophan (W). 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

Uncertain

0.11

BayesDel_noAF

Uncertain

0.12

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.21

Eigen

Uncertain

0.28

Eigen_PC

Uncertain

0.28

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.93

M_CAP

Uncertain

0.21

MetaRNN

Uncertain

0.54

MetaSVM

Uncertain

0.19

MutationAssessor

Benign

1.8

PrimateAI

Uncertain

0.63

PROVEAN

Uncertain

-3.6

REVEL

Pathogenic

0.66

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.018

Polyphen

1.0

Vest4

0.37

MutPred

0.54

Loss of stability (P = 0.0481);

MVP

0.86

MPC

1.8

ClinPred

0.83

GERP RS

3.4

Varity_R

0.34

gMVP

0.57

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