14-24162251-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_006084.5(IRF9):​c.107C>T​(p.Thr36Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. T36T) has been classified as Benign.

Frequency

Genomes: not found (cov: 32)

Consequence

IRF9
NM_006084.5 missense

Scores

11
6
1

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.52
Variant links:
Genes affected
IRF9 (HGNC:6131): (interferon regulatory factor 9) This gene encodes a member of the interferon regulatory factor (IRF) family, a group of transcription factors with diverse roles, including virus-mediated activation of interferon, and modulation of cell growth, differentiation, apoptosis, and immune system activity. Members of the IRF family are characterized by a conserved N-terminal DNA-binding domain containing tryptophan (W) repeats. Mutations in this gene result in Immunodeficiency 65. [provided by RefSeq, Jul 2020]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.889

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
IRF9NM_006084.5 linkc.107C>T p.Thr36Ile missense_variant Exon 2 of 9 ENST00000396864.8 NP_006075.3 Q00978
IRF9NM_001385400.1 linkc.107C>T p.Thr36Ile missense_variant Exon 2 of 10 NP_001372329.1
IRF9NM_001385401.1 linkc.107C>T p.Thr36Ile missense_variant Exon 2 of 9 NP_001372330.1
IRF9NM_001385402.1 linkc.107C>T p.Thr36Ile missense_variant Exon 2 of 9 NP_001372331.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
IRF9ENST00000396864.8 linkc.107C>T p.Thr36Ile missense_variant Exon 2 of 9 1 NM_006084.5 ENSP00000380073.3 Q00978
ENSG00000259529ENST00000558468.2 linkn.*873C>T non_coding_transcript_exon_variant Exon 22 of 29 2 ENSP00000457512.2 A0A0B4J293
ENSG00000259529ENST00000558468.2 linkn.*873C>T 3_prime_UTR_variant Exon 22 of 29 2 ENSP00000457512.2 A0A0B4J293

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
32

ClinVar

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

Submissions by phenotype

not provided Uncertain:1
Aug 10, 2023
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 1472545). This variant has not been reported in the literature in individuals affected with IRF9-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 36 of the IRF9 protein (p.Thr36Ile). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.74
BayesDel_addAF
Pathogenic
0.41
D
BayesDel_noAF
Pathogenic
0.35
CADD
Uncertain
26
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.90
D;D;D
Eigen
Pathogenic
0.84
Eigen_PC
Pathogenic
0.77
FATHMM_MKL
Uncertain
0.89
D
M_CAP
Uncertain
0.27
D
MetaRNN
Pathogenic
0.89
D;D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
3.1
M;.;.
PrimateAI
Uncertain
0.72
T
PROVEAN
Pathogenic
-4.9
D;D;D
REVEL
Pathogenic
0.83
Sift
Uncertain
0.0020
D;D;D
Sift4G
Uncertain
0.0020
D;D;D
Polyphen
1.0
D;.;.
Vest4
0.72
MutPred
0.58
Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);
MVP
0.88
MPC
1.1
ClinPred
1.0
D
GERP RS
5.6
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.62
gMVP
0.87

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr14-24631460; API