rs1061502

chr11-614318-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001572.5(IRF7):c.535A>G(p.Lys179Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.271 in 1,610,258 control chromosomes in the GnomAD database, including 64,369 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Synonymous variant affecting the same amino acid position (i.e. K179K) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.33 (9408 hom., cov: 33)
  • Exomes 𝑓: 0.27 (54961 hom.)
• Consequence: IRF7 NM_001572.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3 O:1
• Conservation: PhyloP100: -3.69

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=3.8386428E-5).
• BP6: Variant 11-614318-T-C is Benign according to our data. Variant chr11-614318-T-C is described in ClinVar as [Benign]. Clinvar id is 1170388.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.513 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IRF7	NM_001572.5	c.535A>G	p.Lys179Glu	missense_variant	6/11	ENST00000525445.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IRF7	ENST00000525445.6	c.535A>G	p.Lys179Glu	missense_variant	6/11	5	NM_001572.5	P2

Frequencies

GnomAD3 genomes AF: 0.325 AC: 49409 AN: 151960 Hom.: 9392 Cov.: 33

Gnomad AFR AF: 0.519

Gnomad AMI AF: 0.208

Gnomad AMR AF: 0.306

Gnomad ASJ AF: 0.347

Gnomad EAS AF: 0.0257

Gnomad SAS AF: 0.129

Gnomad FIN AF: 0.185

Gnomad MID AF: 0.338

Gnomad NFE AF: 0.270

Gnomad OTH AF: 0.333

GnomAD3 exomes AF: 0.253 AC: 61686 AN: 243768 Hom.: 9205 AF XY: 0.242 AC XY: 32092 AN XY: 132454

Gnomad AFR exome AF: 0.524

Gnomad AMR exome AF: 0.323

Gnomad ASJ exome AF: 0.334

Gnomad EAS exome AF: 0.0280

Gnomad SAS exome AF: 0.140

Gnomad FIN exome AF: 0.188

Gnomad NFE exome AF: 0.266

Gnomad OTH exome AF: 0.259

GnomAD4 exome AF: 0.265 AC: 386586 AN: 1458180 Hom.: 54961 Cov.: 41 AF XY: 0.261 AC XY: 188953 AN XY: 725208

Gnomad4 AFR exome AF: 0.523

Gnomad4 AMR exome AF: 0.321

Gnomad4 ASJ exome AF: 0.335

Gnomad4 EAS exome AF: 0.0229

Gnomad4 SAS exome AF: 0.143

Gnomad4 FIN exome AF: 0.198

Gnomad4 NFE exome AF: 0.274

Gnomad4 OTH exome AF: 0.273

GnomAD4 genome AF: 0.325 AC: 49460 AN: 152078 Hom.: 9408 Cov.: 33 AF XY: 0.315 AC XY: 23381 AN XY: 74340

Gnomad4 AFR AF: 0.519

Gnomad4 AMR AF: 0.307

Gnomad4 ASJ AF: 0.347

Gnomad4 EAS AF: 0.0258

Gnomad4 SAS AF: 0.127

Gnomad4 FIN AF: 0.185

Gnomad4 NFE AF: 0.270

Gnomad4 OTH AF: 0.331

Alfa AF: 0.275 Hom.: 4347

Bravo AF: 0.346

TwinsUK AF: 0.268 AC: 995

ALSPAC AF: 0.278 AC: 1073

ESP6500AA AF: 0.524 AC: 2304

ESP6500EA AF: 0.292 AC: 2507

ExAC AF: 0.252 AC: 30382

Asia WGS AF: 0.126 AC: 439 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Immunodeficiency 39 Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Jan 24, 2024

This variant is classified as Benign based on local population frequency. This variant was detected in 59% of patients studied by a panel of primary immunodeficiencies. Number of patients: 56. Only high quality variants are reported. -

not provided Other:1

not provided, no classification provided

phenotyping only

GenomeConnect, ClinGen

-

Variant interpreted as Benign and reported on 04-27-2020 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. This variant was reported in an individual referred for clinical diagnostic genetic testing. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.42
Cadd	Benign	0.0030
Dann	Benign	0.46
DEOGEN2	Benign	0.036	T;.;.;T;T;.
Eigen	Benign	-2.1
Eigen_PC	Benign	-2.1
FATHMM_MKL	Benign	0.032	N
MetaRNN	Benign	0.000038	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.76	N;.;N;N;.;.
MutationTaster	Benign	1.0	P;P;P;P;P;P;P
PrimateAI	Benign	0.46	T
PROVEAN	Benign	0.48	N;N;N;.;.;N
REVEL	Benign	0.26
Sift	Benign	1.0	T;T;T;.;.;T
Sift4G	Benign	1.0	T;T;T;.;T;T
Polyphen		0.0	B;B;B;B;.;B
Vest4		0.048
MPC		0.15
ClinPred		0.0010	T
GERP RS		-5.2
Varity_R		0.038
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: rs1061502; hg19: chr11-614318; COSMIC: COSV52752153; COSMIC: COSV52752153;