7-128947288-G-C

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001098629.3(IRF5):​c.540G>C​(p.Lys180Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000416 in 1,609,830 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000040 ( 0 hom. )

Consequence

IRF5
NM_001098629.3 missense

Scores

3
16

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.53

Publications

0 publications found
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]
IRF5 Gene-Disease associations (from GenCC):
  • systemic lupus erythematosus
    Inheritance: Unknown Classification: SUPPORTIVE Submitted by: Orphanet

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.064514816).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
IRF5NM_001098629.3 linkc.540G>C p.Lys180Asn missense_variant Exon 6 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.540G>C p.Lys180Asn missense_variant Exon 6 of 9 1 NM_001098629.3 ENSP00000349770.5 Q13568-2

Frequencies

GnomAD3 genomes
AF:
0.0000529
AC:
8
AN:
151184
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000146
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000131
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:
0.00
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.000190
AC:
46
AN:
241784
AF XY:
0.000144
show subpopulations
Gnomad AFR exome
AF:
0.0000667
Gnomad AMR exome
AF:
0.00129
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000405
AC:
59
AN:
1458528
Hom.:
0
Cov.:
31
AF XY:
0.0000358
AC XY:
26
AN XY:
725378
show subpopulations
African (AFR)
AF:
0.0000897
AC:
3
AN:
33436
American (AMR)
AF:
0.00121
AC:
54
AN:
44470
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
25982
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39652
South Asian (SAS)
AF:
0.0000116
AC:
1
AN:
85856
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
52276
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5688
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
1110930
Other (OTH)
AF:
0.0000166
AC:
1
AN:
60238
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.527
Heterozygous variant carriers
0
4
7
11
14
18
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
4
8
12
16
20
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.0000529
AC:
8
AN:
151302
Hom.:
0
Cov.:
32
AF XY:
0.0000406
AC XY:
3
AN XY:
73904
show subpopulations
African (AFR)
AF:
0.000146
AC:
6
AN:
41118
American (AMR)
AF:
0.000131
AC:
2
AN:
15240
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3464
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5132
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4766
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10510
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
294
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
67772
Other (OTH)
AF:
0.00
AC:
0
AN:
2096
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.519
Heterozygous variant carriers
0
1
2
2
3
4
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.00
Hom.:
0
Bravo
AF:
0.0000982
ESP6500AA
AF:
0.000231
AC:
1
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.0000990
AC:
12

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Feb 20, 2025
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The c.540G>C (p.K180N) alteration is located in exon 6 (coding exon 5) of the IRF5 gene. This alteration results from a G to C substitution at nucleotide position 540, causing the lysine (K) at amino acid position 180 to be replaced by an asparagine (N). 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
0.14
BayesDel_addAF
Benign
-0.26
T
BayesDel_noAF
Benign
-0.19
CADD
Benign
21
DANN
Benign
0.83
DEOGEN2
Benign
0.11
.;.;T;T;T
Eigen
Benign
-0.34
Eigen_PC
Benign
-0.24
FATHMM_MKL
Uncertain
0.84
D
LIST_S2
Benign
0.78
.;T;.;T;.
M_CAP
Benign
0.056
D
MetaRNN
Benign
0.065
T;T;T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
0.0
.;.;N;N;N
PhyloP100
1.5
PrimateAI
Uncertain
0.60
T
PROVEAN
Benign
0.20
.;N;N;N;N
REVEL
Uncertain
0.32
Sift
Benign
0.31
.;T;T;T;T
Sift4G
Benign
0.52
.;T;T;T;T
Polyphen
1.0
D;D;P;P;P
Vest4
0.62, 0.57, 0.57
MutPred
0.29
.;.;Loss of methylation at K164 (P = 0.0045);Loss of methylation at K164 (P = 0.0045);Loss of methylation at K164 (P = 0.0045);
MVP
0.80
MPC
0.053
ClinPred
0.036
T
GERP RS
3.2
Varity_R
0.072
gMVP
0.26
Mutation Taster
=83/17
polymorphism

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.060
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

dbSNP: rs370799034; hg19: chr7-128587342; API