rs201379782
Variant summary
Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2
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. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_001572.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
IRF7 | NM_001572.5 | c.739G>A | p.Gly247Arg | missense_variant | 7/11 | ENST00000525445.6 | NP_001563.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
IRF7 | ENST00000525445.6 | c.739G>A | p.Gly247Arg | missense_variant | 7/11 | 5 | NM_001572.5 | ENSP00000434009 | P2 |
Frequencies
GnomAD3 genomes AF: 0.000606 AC: 92AN: 151910Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000717 AC: 165AN: 230188Hom.: 0 AF XY: 0.000725 AC XY: 92AN XY: 126978
GnomAD4 exome AF: 0.000520 AC: 757AN: 1454912Hom.: 5 Cov.: 34 AF XY: 0.000554 AC XY: 401AN XY: 723770
GnomAD4 genome AF: 0.000599 AC: 91AN: 152028Hom.: 0 Cov.: 32 AF XY: 0.000632 AC XY: 47AN XY: 74336
ClinVar
Submissions by phenotype
Immunodeficiency 39 Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 13, 2024 | This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 260 of the IRF7 protein (p.Gly260Arg). This variant is present in population databases (rs201379782, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with IRF7-related conditions. ClinVar contains an entry for this variant (Variation ID: 569741). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The arginine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago | Mar 02, 2022 | IRF7 NM_004031.2 exon 5 p.Gly260Arg (c.778G>A): This variant has not been reported in the literature but is present in 0.1% (18/10608) of European alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/11-613978-C-T?dataset=gnomad_r3). This variant is present in ClinVar (Variation ID:569741). This variant amino acid Arginine (Arg) is present in several species including multiple mammals and is not well conserved among evolutionarily distant species; this suggests that this variant may not impact the protein. Additional computational prediction tools do not suggest an impact. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Mar 18, 2022 | - - |
not provided Uncertain:1Benign:2
Uncertain significance, criteria provided, single submitter | not provided | Breakthrough Genomics, Breakthrough Genomics | - | - - |
Likely benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 22, 2021 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
IRF7-related disorder Benign:1
Likely benign, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Feb 03, 2022 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at