rs878855081
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PP3_ModeratePP5
The NM_024306.5(FA2H):āc.691T>Cā(p.Tyr231His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000744 in 1,613,860 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 Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_024306.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FA2H | NM_024306.5 | c.691T>C | p.Tyr231His | missense_variant | 5/7 | ENST00000219368.8 | |
FA2H | XM_011523317.4 | c.691T>C | p.Tyr231His | missense_variant | 5/6 | ||
FA2H | XM_011523319.3 | c.451T>C | p.Tyr151His | missense_variant | 5/7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FA2H | ENST00000219368.8 | c.691T>C | p.Tyr231His | missense_variant | 5/7 | 1 | NM_024306.5 | P1 | |
FA2H | ENST00000569949.1 | c.493T>C | p.Tyr165His | missense_variant | 5/5 | 4 | |||
FA2H | ENST00000567683.5 | c.441T>C | p.Ser147= | synonymous_variant, NMD_transcript_variant | 3/5 | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152142Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251216Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135782
GnomAD4 exome AF: 0.00000753 AC: 11AN: 1461718Hom.: 0 Cov.: 33 AF XY: 0.00000963 AC XY: 7AN XY: 727152
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152142Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74328
ClinVar
Submissions by phenotype
Spastic paraplegia Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jun 25, 2023 | This missense change has been observed in individuals with clinical features of hereditary spastic paraplegia (Invitae). This variant is present in population databases (no rsID available, gnomAD 0.003%). This sequence change replaces tyrosine, which is neutral and polar, with histidine, which is basic and polar, at codon 231 of the FA2H protein (p.Tyr231His). ClinVar contains an entry for this variant (Variation ID: 241464). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. 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 expected to disrupt FA2H protein function. - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Apr 19, 2021 | Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; 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 | Apr 21, 2023 | Variant summary: FA2H c.691T>C (p.Tyr231His) results in a conservative amino acid change located in the Fatty acid hydroxylase domain (IPR006694) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251216 control chromosomes (gnomAD). 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.691T>C in individuals affected with Hereditary Spastic Paraplegia 35 and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=1) and likely pathogenic (n=2). Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Hereditary spastic paraplegia Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, The Hospital for Sick Children | Jun 05, 2017 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at