chr16-74719125-C-T
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4
The NM_024306.5(FA2H):c.649G>A(p.Gly217Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000254 in 1,613,804 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_024306.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
FA2H | NM_024306.5 | c.649G>A | p.Gly217Arg | missense_variant | Exon 5 of 7 | ENST00000219368.8 | NP_077282.3 | |
FA2H | XM_011523317.4 | c.649G>A | p.Gly217Arg | missense_variant | Exon 5 of 6 | XP_011521619.1 | ||
FA2H | XM_011523319.3 | c.409G>A | p.Gly137Arg | missense_variant | Exon 5 of 7 | XP_011521621.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
FA2H | ENST00000219368.8 | c.649G>A | p.Gly217Arg | missense_variant | Exon 5 of 7 | 1 | NM_024306.5 | ENSP00000219368.3 | ||
FA2H | ENST00000569949.1 | c.451G>A | p.Gly151Arg | missense_variant | Exon 5 of 5 | 4 | ENSP00000464576.1 | |||
FA2H | ENST00000567683.5 | n.399G>A | non_coding_transcript_exon_variant | Exon 3 of 5 | 2 | ENSP00000455126.1 |
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152202Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000797 AC: 2AN: 250852Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135598
GnomAD4 exome AF: 0.0000253 AC: 37AN: 1461484Hom.: 0 Cov.: 33 AF XY: 0.0000234 AC XY: 17AN XY: 727020
GnomAD4 genome AF: 0.0000263 AC: 4AN: 152320Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3AN XY: 74486
ClinVar
Submissions by phenotype
Hereditary spastic paraplegia 35 Pathogenic:1
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not specified Uncertain:1
Variant summary: FA2H c.649G>A (p.Gly217Arg) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 250852 control chromosomes (gnomAD). c.649G>A has been reported in the literature as a homozygous genotype in a comprehensively genotyped individual of Pakistani ethnicity affected with Hereditary Spastic Paraplegia 35 (Chrestian_2017) and as an uninformative genotype (i.e. zygosity not specified) in at least one other individual affected with Hereditary Spastic Paraplegia who underwent multigene panel testing (Mereaux_2022). These data indicate that the variant may be associated with disease. 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: 27957547, 34983064). ClinVar contains an entry for this variant (Variation ID: 241463). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -
Spastic paraplegia Uncertain:1
This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 217 of the FA2H protein (p.Gly217Arg). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with hereditary spastic paraplegia (PMID: 27957547, 37410270; internal data). ClinVar contains an entry for this variant (Variation ID: 241463). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt FA2H protein function with a negative predictive value of 80%. 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. -
Hereditary spastic paraplegia Uncertain:1
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not provided Uncertain:1
PM2 -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at