chr4-184408164-T-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_002199.4(IRF2):​c.523A>T​(p.Ile175Phe) variant causes a missense change. The variant allele was found at a frequency of 0.000707 in 1,579,188 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00038 ( 1 hom., cov: 32)
Exomes 𝑓: 0.00074 ( 1 hom. )

Consequence

IRF2
NM_002199.4 missense

Scores

6
13

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.75
Variant links:
Genes affected
IRF2 (HGNC:6117): (interferon regulatory factor 2) IRF2 encodes interferon regulatory factor 2, a member of the interferon regulatory transcription factor (IRF) family. IRF2 competitively inhibits the IRF1-mediated transcriptional activation of interferons alpha and beta, and presumably other genes that employ IRF1 for transcription activation. However, IRF2 also functions as a transcriptional activator of histone H4. [provided by RefSeq, Jul 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.06925094).
BS2
High AC in GnomAd4 at 58 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
IRF2NM_002199.4 linkuse as main transcriptc.523A>T p.Ile175Phe missense_variant 6/9 ENST00000393593.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
IRF2ENST00000393593.8 linkuse as main transcriptc.523A>T p.Ile175Phe missense_variant 6/91 NM_002199.4 P1P14316-1

Frequencies

GnomAD3 genomes
AF:
0.000381
AC:
58
AN:
152194
Hom.:
1
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000121
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:
0.000735
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.000283
AC:
71
AN:
250498
Hom.:
0
AF XY:
0.000296
AC XY:
40
AN XY:
135318
show subpopulations
Gnomad AFR exome
AF:
0.000123
Gnomad AMR exome
AF:
0.000146
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:
0.000538
Gnomad OTH exome
AF:
0.000491
GnomAD4 exome
AF:
0.000742
AC:
1059
AN:
1426876
Hom.:
1
Cov.:
25
AF XY:
0.000708
AC XY:
504
AN XY:
712216
show subpopulations
Gnomad4 AFR exome
AF:
0.0000611
Gnomad4 AMR exome
AF:
0.000180
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000949
Gnomad4 OTH exome
AF:
0.000405
GnomAD4 genome
AF:
0.000381
AC:
58
AN:
152312
Hom.:
1
Cov.:
32
AF XY:
0.000295
AC XY:
22
AN XY:
74476
show subpopulations
Gnomad4 AFR
AF:
0.000120
Gnomad4 AMR
AF:
0.000131
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000735
Gnomad4 OTH
AF:
0.000473
Alfa
AF:
0.000527
Hom.:
0
Bravo
AF:
0.000321
TwinsUK
AF:
0.00108
AC:
4
ALSPAC
AF:
0.00104
AC:
4
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000581
AC:
5
ExAC
AF:
0.000296
AC:
36
EpiCase
AF:
0.000819
EpiControl
AF:
0.000712

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 submitterclinical testingAmbry GeneticsNov 30, 2022The c.523A>T (p.I175F) alteration is located in exon 6 (coding exon 5) of the IRF2 gene. This alteration results from a A to T substitution at nucleotide position 523, causing the isoleucine (I) at amino acid position 175 to be replaced by a phenylalanine (F). 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
0.13
BayesDel_addAF
Benign
-0.070
T
BayesDel_noAF
Uncertain
0.020
CADD
Benign
22
DANN
Benign
0.97
DEOGEN2
Benign
0.20
T;.
Eigen
Benign
-0.17
Eigen_PC
Benign
0.019
FATHMM_MKL
Uncertain
0.78
D
LIST_S2
Benign
0.78
T;T
M_CAP
Uncertain
0.12
D
MetaRNN
Benign
0.069
T;T
MetaSVM
Uncertain
0.63
D
MutationAssessor
Benign
1.9
L;.
MutationTaster
Benign
1.0
D
PrimateAI
Uncertain
0.63
T
PROVEAN
Benign
-0.89
N;N
REVEL
Uncertain
0.38
Sift
Benign
0.62
T;T
Sift4G
Benign
0.56
T;.
Polyphen
0.0010
B;.
Vest4
0.29
MVP
0.92
MPC
1.3
ClinPred
0.025
T
GERP RS
5.3
Varity_R
0.065
gMVP
0.32

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: rs139625773; hg19: chr4-185329318; API