NM_001572.5:c.739G>A

Variant names:

• chr11-613978-C-T
• rs201379782
• NM_001572.5:c.739G>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001572.5(IRF7):​c.739G>A​(p.Gly247Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000528 in 1,606,940 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G247E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00060 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00052 (5 hom.)
• Consequence: IRF7 NM_001572.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:4
• Conservation: PhyloP100: -1.28
• Publications: 4 publications found

Genes affected

IRF7 (HGNC:6122): (interferon regulatory factor 7) This gene encodes interferon regulatory factor 7, a member of the interferon regulatory transcription factor (IRF) family. It has been shown to play a role in the transcriptional activation of virus-inducible cellular genes, including interferon beta chain genes. Inducible expression of IRF7 is largely restricted to lymphoid tissue. The encoded protein plays an important role in the innate immune response against DNA and RNA viruses. [provided by RefSeq, Jul 2021]

IRF7 Gene-Disease associations (from GenCC):

• immunodeficiency 39

  Inheritance: AR Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007898957).
• BS2: High Homozygotes in GnomAdExome4 at 5 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001572.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IRF7	NM_001572.5	MANE Select	c.739G>A	p.Gly247Arg	missense	Exon 7 of 11	NP_001563.2
	IRF7	NM_004031.4		c.778G>A	p.Gly260Arg	missense	Exon 6 of 10	NP_004022.2	Q92985-4
	IRF7	NM_001440440.1		c.775G>A	p.Gly259Arg	missense	Exon 6 of 10	NP_001427369.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IRF7	ENST00000525445.6	TSL:5 MANE Select	c.739G>A	p.Gly247Arg	missense	Exon 7 of 11	ENSP00000434009.2	Q92985-1
	IRF7	ENST00000397566.5	TSL:1	c.778G>A	p.Gly260Arg	missense	Exon 5 of 9	ENSP00000380697.1	Q92985-4
	IRF7	ENST00000397570.5	TSL:1	c.719-113G>A		intron	N/A	ENSP00000380700.2	M9RSF4

Frequencies

GnomAD3 genomes AF: 0.000606 AC: 92 AN: 151910 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000726

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00170

Gnomad MID AF: 0.00637

Gnomad NFE AF: 0.000486

Gnomad OTH AF: 0.00192

GnomAD2 exomes AF: 0.000717 AC: 165 AN: 230188 AF XY: 0.000725

Gnomad AFR exome AF: 0.0000718

Gnomad AMR exome AF: 0.000831

Gnomad ASJ exome AF: 0.00160

Gnomad EAS exome AF: 0.0000565

Gnomad FIN exome AF: 0.00117

Gnomad NFE exome AF: 0.000713

Gnomad OTH exome AF: 0.00269

GnomAD4 exome AF: 0.000520 AC: 757 AN: 1454912 Hom.: 5 Cov.: 34 AF XY: 0.000554 AC XY: 401 AN XY: 723770

African (AFR) AF: 0.000241 AC: 8 AN: 33178

American (AMR) AF: 0.00116 AC: 50 AN: 43046

Ashkenazi Jewish (ASJ) AF: 0.00105 AC: 27 AN: 25816

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39652

South Asian (SAS) AF: 0.000537 AC: 46 AN: 85652

European-Finnish (FIN) AF: 0.000812 AC: 42 AN: 51698

Middle Eastern (MID) AF: 0.0159 AC: 91 AN: 5738

European-Non Finnish (NFE) AF: 0.000369 AC: 410 AN: 1110072

Other (OTH) AF: 0.00137 AC: 82 AN: 60060

GnomAD4 genome AF: 0.000599 AC: 91 AN: 152028 Hom.: 0 Cov.: 32 AF XY: 0.000632 AC XY: 47 AN XY: 74336

African (AFR) AF: 0.0000724 AC: 3 AN: 41462

American (AMR) AF: 0.00131 AC: 20 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00202 AC: 7 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5152

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4816

European-Finnish (FIN) AF: 0.00170 AC: 18 AN: 10608

Middle Eastern (MID) AF: 0.00685 AC: 2 AN: 292

European-Non Finnish (NFE) AF: 0.000486 AC: 33 AN: 67922

Other (OTH) AF: 0.00142 AC: 3 AN: 2110

Alfa AF: 0.000520 Hom.: 0

Bravo AF: 0.000525

ESP6500AA AF: 0.000229 AC: 1

ESP6500EA AF: 0.000585 AC: 5

ExAC AF: 0.000631 AC: 76

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	3	-	Immunodeficiency 39 (3)
-	1	2	not provided (3)
-	-	1	IRF7-related disorder (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	0.13
DANN	Benign	0.58
DEOGEN2	Benign	0.057	T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.019	N
LIST_S2	Benign	0.61	T
M_CAP	Benign	0.036	D
MetaRNN	Benign	0.0079	T
MetaSVM	Uncertain	-0.080	T
MutationAssessor	Benign	0.14	N
PhyloP100		-1.3
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.10	N
REVEL	Benign	0.21
Sift	Benign	0.56	T
Sift4G	Benign	0.49	T
Polyphen		0.0	B
Vest4		0.13
MutPred		0.27		Loss of catalytic residue at Q249 (P = 0.0895)
MVP		0.52
MPC		0.13
ClinPred		0.0095	T
GERP RS		-5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.068
gMVP		0.34
Mutation Taster		=96/4	polymorphism

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

Other links and lift over

dbSNP: rs201379782; hg19: chr11-613978; COSMIC: COSV52756792; COSMIC: COSV52756792;