rs774453718

Variant summary

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

The NM_001098629.3(IRF5):​c.248C>T​(p.Pro83Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 1,613,262 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

IRF5
NM_001098629.3 missense

Scores

10
8
1

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.57
Variant links:
Genes affected
IRF5 (HGNC:6120): (interferon regulatory factor 5) 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. Alternative promoter use and alternative splicing result in multiple transcript variants, and a 30-nt indel polymorphism (SNP rs60344245) can result in loss of a 10-aa segment. [provided by RefSeq, Dec 2016]

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, 0.919

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
IRF5NM_001098629.3 linkc.248C>T p.Pro83Leu missense_variant Exon 3 of 9 ENST00000357234.10 NP_001092099.1 Q13568-2B7Z1M2C9JAU6

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
IRF5ENST00000357234.10 linkc.248C>T p.Pro83Leu missense_variant Exon 3 of 9 1 NM_001098629.3 ENSP00000349770.5 Q13568-2

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152228
Hom.:
0
Cov.:
32
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:
0.000188
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000399
AC:
1
AN:
250316
Hom.:
0
AF XY:
0.00000739
AC XY:
1
AN XY:
135350
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:
0.00
Gnomad FIN exome
AF:
0.0000464
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000274
AC:
4
AN:
1461034
Hom.:
0
Cov.:
31
AF XY:
0.00000550
AC XY:
4
AN XY:
726850
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:
0.00
Gnomad4 FIN exome
AF:
0.0000188
Gnomad4 NFE exome
AF:
0.00000270
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152228
Hom.:
0
Cov.:
32
AF XY:
0.0000269
AC XY:
2
AN XY:
74374
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:
0.000188
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
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
Sep 26, 2024
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Variant summary: IRF5 c.248C>T (p.Pro83Leu) results in a non-conservative amino acid change located in the DNA-binding domain (IPR001346) of the encoded protein sequence. Four of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 250316 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.248C>T in individuals affected with IRF5-Related Disorders and no experimental evidence demonstrating its impact on protein function have been reported. No submitters have cited clinical-significance assessments for this variant to ClinVar. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.91
BayesDel_addAF
Pathogenic
0.54
D
BayesDel_noAF
Pathogenic
0.53
CADD
Pathogenic
31
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.80
.;.;.;.;D;D;D;D;D;.
Eigen
Uncertain
0.57
Eigen_PC
Uncertain
0.43
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Uncertain
0.97
.;D;D;D;D;D;.;D;.;D
M_CAP
Pathogenic
0.39
D
MetaRNN
Pathogenic
0.92
D;D;D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Uncertain
2.8
M;.;M;M;.;.;M;M;M;M
PrimateAI
Uncertain
0.73
T
PROVEAN
Pathogenic
-9.9
D;.;D;D;D;D;D;D;D;.
REVEL
Pathogenic
0.86
Sift
Pathogenic
0.0
D;.;D;D;D;D;D;D;D;.
Sift4G
Uncertain
0.017
D;D;D;D;D;D;D;D;D;D
Polyphen
1.0
D;.;D;.;.;.;D;D;D;.
Vest4
0.88, 0.77, 0.82, 0.78, 0.77, 0.93
MutPred
0.70
Loss of ubiquitination at K85 (P = 0.0376);Loss of ubiquitination at K85 (P = 0.0376);Loss of ubiquitination at K85 (P = 0.0376);Loss of ubiquitination at K85 (P = 0.0376);Loss of ubiquitination at K85 (P = 0.0376);Loss of ubiquitination at K85 (P = 0.0376);Loss of ubiquitination at K85 (P = 0.0376);Loss of ubiquitination at K85 (P = 0.0376);Loss of ubiquitination at K85 (P = 0.0376);Loss of ubiquitination at K85 (P = 0.0376);
MVP
0.89
MPC
1.7
ClinPred
1.0
D
GERP RS
5.1
Varity_R
0.79
gMVP
0.89

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.

Other links and lift over

dbSNP: rs774453718; hg19: chr7-128585951; API