Variant chr12-6548801-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_001193457.2(IFFO1):c.1129C>T(p.Arg377Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000347 in 1,613,358 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000038 ( 1 hom. )

Consequence

IFFO1
NM_001193457.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.54

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]

IFFO1 links:

IFFO1 (HGNC:):

IFFO1 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.764

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IFFO1	NM_001193457.2 linkuse as main transcript	c.1129C>T	p.Arg377Trp	missense_variant	6/10	ENST00000619571.5	NP_001180386.1	A0A087WZ16Q9Y4M3B4DQQ1Q6P593

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IFFO1	ENST00000619571.5 linkuse as main transcript	c.1129C>T	p.Arg377Trp	missense_variant	6/10	2	NM_001193457.2	ENSP00000482285.1		A0A087WZ16

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152134

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000205

AC:

AN:

243904

Hom.:

AF XY:

0.0000302

AC XY:

AN XY:

132396

show subpopulations

Gnomad AFR exome

AF:

0.0000634

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000469

Gnomad NFE exome

AF:

0.0000278

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000376

AC:

AN:

1461224

Hom.:

Cov.:

AF XY:

0.0000330

AC XY:

AN XY:

726868

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000753

Gnomad4 NFE exome

AF:

0.0000450

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152134

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74310

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

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

Alfa

AF:

0.0000162

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.0000330

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 16, 2024

The c.1129C>T (p.R377W) alteration is located in exon 6 (coding exon 6) of the IFFO1 gene. This alteration results from a C to T substitution at nucleotide position 1129, causing the arginine (R) at amino acid position 377 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

0.32

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Pathogenic

0.16

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.099

.;T;.;T;.;.;.

Eigen

Uncertain

0.39

Eigen_PC

Uncertain

0.33

FATHMM_MKL

Uncertain

0.82

LIST_S2

Uncertain

0.96

.;D;D;D;D;D;D

M_CAP

Pathogenic

0.42

MetaRNN

Pathogenic

0.76

D;D;D;D;D;D;D

MetaSVM

Uncertain

0.56

MutationAssessor

Benign

1.9

.;.;.;L;.;.;.

PrimateAI

Uncertain

0.76

PROVEAN

Uncertain

-3.3

D;D;D;D;.;D;.

REVEL

Uncertain

0.57

Sift

Pathogenic

0.0

D;D;D;D;.;D;.

Sift4G

Pathogenic

0.0010

D;D;D;D;D;D;D

Polyphen

1.0

.;.;D;D;.;D;.

Vest4

0.64

MutPred

0.53

.;.;.;Loss of ubiquitination at K365 (P = 0.0618);.;.;.;

MVP

0.84

MPC

1.5

ClinPred

0.74

GERP RS

2.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.11

gMVP

0.67

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

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