rs587781260
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_001199138.2(NLRC4):c.1022T>C(p.Val341Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V341L) has been classified as Pathogenic.
Frequency
Consequence
NM_001199138.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NLRC4 | NM_001199138.2 | c.1022T>C | p.Val341Ala | missense_variant | 4/9 | ENST00000402280.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NLRC4 | ENST00000402280.6 | c.1022T>C | p.Val341Ala | missense_variant | 4/9 | 1 | NM_001199138.2 | P1 | |
ENST00000697331.1 | n.2994-2493A>G | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Cov.: 40
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Periodic fever-infantile enterocolitis-autoinflammatory syndrome Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Oct 01, 2014 | - - |
Syndrome of entercolitis and autoinflmmation caused by mutation of NLRC4 (SCAN4) Pathogenic:1
Pathogenic, criteria provided, single submitter | research | Richard Lifton Laboratory, Yale University School of Medicine | Jul 18, 2014 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 11, 2015 | The V341A variant in the NLRC4 gene has been reported previously in a family with enterocolitis andautoinflammation (Romberg et al., 2014). The variant occurred de novo in the father and was inheritedby two of his sons, presentation of the disease was variable, with death from diffuse alveolar hemorrhageoccurring at 26 days of life in the most severely affected son (Romberg et al., 2014). The V341A substitutionwas not observed in approximately 6500 individuals of European and African American ancestry in theNHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. TheV341A variant is a conservative amino acid substitution and occurs at a position that is conserved acrossspecies. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging tothe protein structure/function. A missense de novo variant in a nearby residue (T337S) has been reportedin a patient with autoinflammation with recurrent macrophage activation syndrome (Canna et al., 2014),supporting the functional importance of this region of the protein. Therefore, we interpret this variant as pathogenic. - |
Periodic fever-infantile enterocolitis-autoinflammatory syndrome;C4015276:Familial cold autoinflammatory syndrome 4 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 30, 2020 | This variant is not present in population databases (ExAC no frequency). This sequence change replaces valine with alanine at codon 341 of the NLRC4 protein (p.Val341Ala). The valine residue is highly conserved and there is a small physicochemical difference between valine and alanine. This variant has been observed in individual(s) with autoinflammation with infantile enterocolitis (PMID: 25217960, 30864118). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 143224). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this variant affects NLRC4 protein function (PMID: 25217960, 29778503). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at