4-184408164-T-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.75

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]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IRF2	NM_002199.4	c.523A>T	p.Ile175Phe	missense_variant	6/9	ENST00000393593.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IRF2	ENST00000393593.8	c.523A>T	p.Ile175Phe	missense_variant	6/9	1	NM_002199.4	P1

Frequencies

GnomAD3 genomes AF: 0.000381 AC: 58 AN: 152194 Hom.: 1 Cov.: 32

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

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

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

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

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 30, 2022

The 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

Other links and lift over

dbSNP: rs139625773; hg19: chr4-185329318;