rs35744605
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 8P and 8B. PVS1BS1BS2
The NM_022168.4(IFIH1):c.1879G>T(p.Glu627*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00517 in 1,611,082 control chromosomes in the GnomAD database, including 30 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_022168.4 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00358 AC: 545AN: 152142Hom.: 4 Cov.: 32
GnomAD3 exomes AF: 0.00318 AC: 797AN: 250898Hom.: 1 AF XY: 0.00318 AC XY: 431AN XY: 135614
GnomAD4 exome AF: 0.00534 AC: 7792AN: 1458822Hom.: 26 Cov.: 30 AF XY: 0.00526 AC XY: 3821AN XY: 725876
GnomAD4 genome AF: 0.00358 AC: 545AN: 152260Hom.: 4 Cov.: 32 AF XY: 0.00316 AC XY: 235AN XY: 74446
ClinVar
Submissions by phenotype
not provided Uncertain:1Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics | Jan 10, 2017 | - - |
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Nov 01, 2024 | IFIH1: BS2 - |
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Sep 15, 2023 | BS2, PS3, PVS1 - |
IFIH1-related immunodeficiency Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Undiagnosed Diseases Network, NIH | Sep 18, 2018 | - - |
Inborn genetic diseases Benign:1
Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 17, 2022 | This alteration is classified as 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. - |
Aicardi-Goutieres syndrome 7;C4225427:Singleton-Merten syndrome 1;C5676929:Immunodeficiency 95 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago | Oct 05, 2022 | This variant has been reported in the literature in multiple individuals, largely in the context as a risk modifier for a variety of conditions such as type I diabetes and inflammatory bowel disease (Nejentsev 2009 PMID:19264985, Chistiakov 2010 PMID:20736039, Ostrowski 2016 PMID:28008999, Asgari 2017 PMID:28716935, Cananzi 2021 PMID:34185153). This variant is present in the Genome Aggregation Database (Highest reported MAF 0.6% (418/68032) including 3 homozygotes (https://gnomad.broadinstitute.org/variant/2-162277580-C-A?dataset=gnomad_r3). This variant is present in ClinVar, with several labs classifying this variant as Likely Benign or Benign (Variation ID:377048). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. This variant creates a premature stop at this codon which results in an absent or abnormal protein. Functional studies support a deleterious effect of this variant (Shigemoto 2018 PMID:19324880, Cananzi 2021 PMID:34185153). However, these studies may not accurately represent in vivo biological function. Although an impact to the protein is expected due to this variant, the high presence of the variant and homozygotes in control cohorts as well as the multiple entries of Likely Benign or Benign in ClinVar suggest that the effect of this variant is more akin to a risk allele vs. a mendelian disease allele. Therefore, this variant is classified as Likely Benign. - |
Aicardi-Goutieres syndrome 7 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Jan 01, 2019 | - - |
Aicardi-Goutieres syndrome 7;C4225427:Singleton-Merten syndrome 1 Benign:1
Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 30, 2024 | - - |
Singleton-Merten syndrome 1 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
IFIH1-related disorder Benign:1
Likely benign, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Sep 10, 2020 | 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