chr4-184408172-G-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_002199.4(IRF2):​c.515C>T​(p.Thr172Met) variant causes a missense change. The variant allele was found at a frequency of 0.00000877 in 1,595,958 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000090 ( 0 hom. )

Consequence

IRF2
NM_002199.4 missense

Scores

2
15
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.91
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 -4 ACMG points.

BS2
High AC in GnomAdExome4 at 13 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
IRF2NM_002199.4 linkuse as main transcriptc.515C>T p.Thr172Met missense_variant 6/9 ENST00000393593.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
IRF2ENST00000393593.8 linkuse as main transcriptc.515C>T p.Thr172Met missense_variant 6/91 NM_002199.4 P1P14316-1

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152142
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000241
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:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000279
AC:
7
AN:
251266
Hom.:
0
AF XY:
0.0000221
AC XY:
3
AN XY:
135802
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000290
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.0000462
Gnomad NFE exome
AF:
0.0000352
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000900
AC:
13
AN:
1443816
Hom.:
0
Cov.:
27
AF XY:
0.0000111
AC XY:
8
AN XY:
719724
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.0000187
Gnomad4 NFE exome
AF:
0.00000822
Gnomad4 OTH exome
AF:
0.0000167
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152142
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74316
show subpopulations
Gnomad4 AFR
AF:
0.0000241
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:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000378
ExAC
AF:
0.0000330
AC:
4

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 GeneticsDec 17, 2023The c.515C>T (p.T172M) alteration is located in exon 6 (coding exon 5) of the IRF2 gene. This alteration results from a C to T substitution at nucleotide position 515, causing the threonine (T) at amino acid position 172 to be replaced by a methionine (M). 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
Uncertain
0.35
BayesDel_addAF
Pathogenic
0.27
D
BayesDel_noAF
Pathogenic
0.26
CADD
Pathogenic
28
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.59
D;.
Eigen
Uncertain
0.26
Eigen_PC
Uncertain
0.37
FATHMM_MKL
Uncertain
0.90
D
LIST_S2
Uncertain
0.87
D;D
M_CAP
Uncertain
0.12
D
MetaRNN
Uncertain
0.52
D;D
MetaSVM
Uncertain
0.61
D
MutationAssessor
Uncertain
2.3
M;.
MutationTaster
Benign
1.0
D
PrimateAI
Uncertain
0.75
T
PROVEAN
Uncertain
-2.8
D;D
REVEL
Uncertain
0.58
Sift
Benign
0.12
T;D
Sift4G
Uncertain
0.033
D;.
Polyphen
0.71
P;.
Vest4
0.48
MutPred
0.38
Loss of glycosylation at T172 (P = 0.1022);Loss of glycosylation at T172 (P = 0.1022);
MVP
0.98
MPC
2.0
ClinPred
0.55
D
GERP RS
5.3
Varity_R
0.097
gMVP
0.55

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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: rs769034903; hg19: chr4-185329326; COSMIC: COSV66931081; COSMIC: COSV66931081; API