rs376452111
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 1P and 7B. PP2BP4_ModerateBS1_SupportingBS2
The NM_005097.4(LGI1):c.398A>G(p.His133Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000483 in 1,613,564 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H133Y) has been classified as Uncertain significance.
Frequency
Consequence
NM_005097.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LGI1 | NM_005097.4 | c.398A>G | p.His133Arg | missense_variant | 4/8 | ENST00000371418.9 | |
LOC105378437 | XR_001747552.2 | n.78-559T>C | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LGI1 | ENST00000371418.9 | c.398A>G | p.His133Arg | missense_variant | 4/8 | 1 | NM_005097.4 | P1 | |
ENST00000627075.1 | n.75-559T>C | intron_variant, non_coding_transcript_variant | 3 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152246Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000199 AC: 5AN: 251038Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135692
GnomAD4 exome AF: 0.0000513 AC: 75AN: 1461318Hom.: 0 Cov.: 30 AF XY: 0.0000468 AC XY: 34AN XY: 727004
GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152246Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74386
ClinVar
Submissions by phenotype
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 04, 2023 | The c.398A>G (p.H133R) alteration is located in exon 4 (coding exon 4) of the LGI1 gene. This alteration results from a A to G substitution at nucleotide position 398, causing the histidine (H) at amino acid position 133 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Autosomal dominant epilepsy with auditory features Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Mar 25, 2023 | 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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt LGI1 protein function. ClinVar contains an entry for this variant (Variation ID: 464749). This variant has not been reported in the literature in individuals affected with LGI1-related conditions. This variant is present in population databases (rs376452111, gnomAD 0.004%). This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 133 of the LGI1 protein (p.His133Arg). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at