NM_014845.6:c.449A>G
Variant summary
Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PP3_Moderate
The NM_014845.6(FIG4):c.449A>G(p.Tyr150Cys) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000499 in 1,201,446 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_014845.6 missense, splice_region
Scores
Clinical Significance
Conservation
Publications
- Charcot-Marie-Tooth diseaseInheritance: AR Classification: DEFINITIVE Submitted by: ClinGen, Illumina
- Charcot-Marie-Tooth disease type 4JInheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics, Laboratory for Molecular Medicine
- Yunis-Varon syndromeInheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, G2P
- amyotrophic lateral sclerosis type 11Inheritance: Unknown, AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Genomics England PanelApp
- amyotrophic lateral sclerosisInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- bilateral parasagittal parieto-occipital polymicrogyriaInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
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ACMG classification
Our verdict: Uncertain_significance. The variant received 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
FIG4 | NM_014845.6 | c.449A>G | p.Tyr150Cys | missense_variant, splice_region_variant | Exon 5 of 23 | ENST00000230124.8 | NP_055660.1 | |
FIG4 | XM_011536281.4 | c.386A>G | p.Tyr129Cys | missense_variant, splice_region_variant | Exon 5 of 23 | XP_011534583.1 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD2 exomes AF: 0.00 AC: 0AN: 236036 AF XY: 0.00
GnomAD4 exome AF: 0.00000499 AC: 6AN: 1201446Hom.: 0 Cov.: 22 AF XY: 0.00000656 AC XY: 4AN XY: 609974 show subpopulations
Age Distribution
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
FIG4-related disorder Uncertain:1
The FIG4 c.449A>G variant is predicted to result in the amino acid substitution p.Tyr150Cys. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -
Charcot-Marie-Tooth disease type 4 Uncertain:1
This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 150 of the FIG4 protein (p.Tyr150Cys). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with FIG4-related conditions. ClinVar contains an entry for this variant (Variation ID: 543435). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at