rs864622744
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PP3_Moderate
The NM_001136472.2(LITAF):c.479G>A(p.Arg160His) variant causes a missense change. The variant allele was found at a frequency of 0.0000093 in 1,612,364 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. R160C) has been classified as Uncertain significance.
Frequency
Consequence
NM_001136472.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LITAF | NM_001136472.2 | c.479G>A | p.Arg160His | missense_variant | 4/4 | ENST00000622633.5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LITAF | ENST00000622633.5 | c.479G>A | p.Arg160His | missense_variant | 4/4 | 1 | NM_001136472.2 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152058Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000160 AC: 4AN: 249474Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 134882
GnomAD4 exome AF: 0.00000822 AC: 12AN: 1460306Hom.: 0 Cov.: 31 AF XY: 0.00000551 AC XY: 4AN XY: 726358
GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152058Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74260
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jun 01, 2022 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Dec 02, 2020 | In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jan 04, 2024 | Variant summary: LITAF c.479G>A (p.Arg160His) results in a non-conservative amino acid change located in the LPS-induced tumour necrosis factor alpha factor (IPR006629) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 249474 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.479G>A in individuals affected with Charcot-Marie Disease Type 1C and no experimental evidence demonstrating its impact on protein function have been reported. Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Charcot-Marie-Tooth disease Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Molecular Genetics Laboratory, London Health Sciences Centre | - | - - |
Charcot-Marie-Tooth disease type 1C Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 28, 2023 | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 160 of the LITAF protein (p.Arg160His). This variant is present in population databases (no rsID available, gnomAD 0.006%). This missense change has been observed in individual(s) with Charcot-Marie-Tooth disease (Invitae). This missense change has been observed in at least one individual who was not affected with LITAF-related conditions (Invitae). ClinVar contains an entry for this variant (Variation ID: 221090). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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. - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 27, 2019 | The p.R160H variant (also known as c.479G>A), located in coding exon 3 of the LITAF gene, results from a G to A substitution at nucleotide position 479. The arginine at codon 160 is replaced by histidine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at