11-615010-G-T

Variant names:

• chr11-615010-G-T
• rs12290989
• NM_001572.5:c.184-3C>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001572.5(IRF7):​c.184-3C>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.272 in 1,542,680 control chromosomes in the GnomAD database, including 62,014 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.32 (9295 hom., cov: 35)
  • Exomes 𝑓: 0.27 (52719 hom.)
• Consequence: IRF7 NM_001572.5 splice_region, intron
• Scores: Splicing: ADA: 0.2375
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.66
• Publications: 14 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 11-615010-G-T is Benign according to our data. Variant chr11-615010-G-T is described in ClinVar as [Benign]. Clinvar id is 1170390.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.511 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IRF7	NM_001572.5	c.184-3C>A		splice_region_variant, intron_variant	Intron 3 of 10	ENST00000525445.6	NP_001563.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IRF7	ENST00000525445.6	c.184-3C>A		splice_region_variant, intron_variant	Intron 3 of 10	5	NM_001572.5	ENSP00000434009.2

Frequencies

GnomAD3 genomes AF: 0.324 AC: 49210 AN: 151888 Hom.: 9279 Cov.: 35

Gnomad AFR AF: 0.517

Gnomad AMI AF: 0.205

Gnomad AMR AF: 0.306

Gnomad ASJ AF: 0.346

Gnomad EAS AF: 0.0258

Gnomad SAS AF: 0.131

Gnomad FIN AF: 0.185

Gnomad MID AF: 0.333

Gnomad NFE AF: 0.270

Gnomad OTH AF: 0.331

GnomAD2 exomes AF: 0.250 AC: 40766 AN: 163132 AF XY: 0.241

Gnomad AFR exome AF: 0.513

Gnomad AMR exome AF: 0.319

Gnomad ASJ exome AF: 0.338

Gnomad EAS exome AF: 0.0283

Gnomad FIN exome AF: 0.187

Gnomad NFE exome AF: 0.262

Gnomad OTH exome AF: 0.256

GnomAD4 exome AF: 0.266 AC: 369805 AN: 1390674 Hom.: 52719 Cov.: 37 AF XY: 0.261 AC XY: 179184 AN XY: 685366

African (AFR) AF: 0.522 AC: 16790 AN: 32174

American (AMR) AF: 0.316 AC: 12303 AN: 38878

Ashkenazi Jewish (ASJ) AF: 0.336 AC: 7688 AN: 22908

East Asian (EAS) AF: 0.0224 AC: 860 AN: 38318

South Asian (SAS) AF: 0.145 AC: 11246 AN: 77298

European-Finnish (FIN) AF: 0.200 AC: 7360 AN: 36858

Middle Eastern (MID) AF: 0.306 AC: 1703 AN: 5562

European-Non Finnish (NFE) AF: 0.274 AC: 296141 AN: 1081022

Other (OTH) AF: 0.273 AC: 15714 AN: 57656

GnomAD4 genome AF: 0.324 AC: 49262 AN: 152006 Hom.: 9295 Cov.: 35 AF XY: 0.313 AC XY: 23292 AN XY: 74338

African (AFR) AF: 0.516 AC: 21374 AN: 41386

American (AMR) AF: 0.306 AC: 4675 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.346 AC: 1200 AN: 3468

East Asian (EAS) AF: 0.0258 AC: 134 AN: 5190

South Asian (SAS) AF: 0.129 AC: 625 AN: 4832

European-Finnish (FIN) AF: 0.185 AC: 1961 AN: 10610

Middle Eastern (MID) AF: 0.341 AC: 99 AN: 290

European-Non Finnish (NFE) AF: 0.270 AC: 18311 AN: 67930

Other (OTH) AF: 0.330 AC: 696 AN: 2112

Alfa AF: 0.301 Hom.: 1409

Bravo AF: 0.345

Asia WGS AF: 0.127 AC: 440 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Immunodeficiency 39 Benign:2

Jul 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Apr 07, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Jan 24, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	18
DANN	Benign	0.84
PhyloP100		1.7
Mutation Taster		=97/3	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.24
dbscSNV1_RF	Benign	0.39
SpliceAI score (max)		0.35		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.35		Position offset: -26
DS_AL_spliceai		0.25		Position offset: -3

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs12290989; hg19: chr11-615010;