rs199475953
Variant names:
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 8P and 5B. PVS1BS1_SupportingBS2
The NM_001199138.2(NLRC4):c.928C>T(p.Arg310*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00015 in 1,613,998 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.00015 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00015 ( 0 hom. )
Consequence
NLRC4
NM_001199138.2 stop_gained
NM_001199138.2 stop_gained
Scores
1
2
3
Clinical Significance
Conservation
PhyloP100: 0.452
Genes affected
NLRC4 (HGNC:16412): (NLR family CARD domain containing 4) This gene encodes a member of the caspase recruitment domain-containing NLR family. Family members play essential roles in innate immune response to a wide range of pathogenic organisms, tissue damage and other cellular stresses. Mutations in this gene result in autoinflammation with infantile enterocolitis. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2014]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 3 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000151 (23/152238) while in subpopulation NFE AF= 0.000279 (19/68012). AF 95% confidence interval is 0.000182. There are 0 homozygotes in gnomad4. There are 9 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
BS2
High AC in GnomAd4 at 23 AD gene.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes 0.000151 AC: 23AN: 152120Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000167 AC: 42AN: 251260Hom.: 0 AF XY: 0.000162 AC XY: 22AN XY: 135784
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GnomAD4 exome AF: 0.000150 AC: 219AN: 1461760Hom.: 0 Cov.: 40 AF XY: 0.000161 AC XY: 117AN XY: 727194
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GnomAD4 genome 0.000151 AC: 23AN: 152238Hom.: 0 Cov.: 32 AF XY: 0.000121 AC XY: 9AN XY: 74444
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:5Benign:1Other:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:2Benign:1Other:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Aug 11, 2019 | - - |
| Uncertain significance, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The NLRC4 p.R310* variant was identified in 1 of 392 proband chromosomes (frequency: 0.00255) from individuals with systemic autoinflammatory diseases (Karacan_2019_PMID:30783801). The variant was also reported in another case study in a female child with an auto-inflammatory syndrome phenotype (Sleptsova_2016). The variant was identified in dbSNP (ID: rs199475953) and ClinVar (classified as uncertain significance by Invitae). The variant was identified in control databases in 48 of 282654 chromosomes at a frequency of 0.0001698 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 40 of 129004 chromosomes (freq: 0.00031), Latino in 5 of 35434 chromosomes (freq: 0.000141), Other in 1 of 7224 chromosomes (freq: 0.000138) and European (Finnish) in 2 of 25110 chromosomes (freq: 0.00008), but was not observed in the African, Ashkenazi Jewish, East Asian, or South Asian populations. The c.928C>T variant leads to a premature stop codon at position 310 which is predicted to lead to a truncated or absent protein and loss of function. The role of NLRC4 loss of function variants in disease is currently not well established. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. - |
| not provided, no classification provided | literature only | Human Evolutionary Genetics, Institut Pasteur | - | - - |
| Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Sep 01, 2024 | NLRC4: BS1 - |
Periodic fever-infantile enterocolitis-autoinflammatory syndrome Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Department of Human Genetics, Hannover Medical School | Nov 14, 2024 | ACMG: none - |
not specified Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 22, 2023 | Variant summary: NLRC4 c.928C>T (p.Arg310X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, however the molecular mechanism of disease attributed to NLRC4 is gain-of-function. The variant allele was found at a frequency of 0.00017 in 251260 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in NLRC4 causing NLRC4-Related Disorders, allowing no conclusion about variant significance. c.928C>T has been reported in the literature in heterozygous individuals affected with clinical features of NLRC4-Related Disorders (e.g., Popplewell_2020, Karacan_2019), however, these report(s) do not provide unequivocal conclusions about association of the variant with NLRC4-Related Disorders. c.928C>T has also been identified in unaffected relatives of affected individuals with the variant (Popplewell_2020). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 30783801, 32529290). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014; two submitters classified it as a variant of uncertain significance, while one classified it as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Periodic fever-infantile enterocolitis-autoinflammatory syndrome;C4015276:Familial cold autoinflammatory syndrome 4 Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 07, 2025 | This sequence change creates a premature translational stop signal (p.Arg310*) in the NLRC4 gene. It is expected to result in an absent or disrupted protein product. However, the current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in NLRC4 cause disease. This variant is present in population databases (rs199475953, gnomAD 0.03%), and has an allele count higher than expected for a pathogenic variant. This premature translational stop signal has been observed in individual(s) with systemic autoinflammatory disease (PMID: 30783801). ClinVar contains an entry for this variant (Variation ID: 103085). 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. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
Vest4
GERP RS
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at