rs1057519235
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1PM2PP3
The NM_024306.5(FA2H):c.205C>T(p.His69Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000718 in 1,393,288 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. H69Q) has been classified as Uncertain significance.
Frequency
Consequence
NM_024306.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FA2H | NM_024306.5 | c.205C>T | p.His69Tyr | missense_variant | 1/7 | ENST00000219368.8 | |
FA2H | XM_011523317.4 | c.205C>T | p.His69Tyr | missense_variant | 1/6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FA2H | ENST00000219368.8 | c.205C>T | p.His69Tyr | missense_variant | 1/7 | 1 | NM_024306.5 | P1 | |
FA2H | ENST00000567683.5 | c.205C>T | p.His69Tyr | missense_variant, NMD_transcript_variant | 1/5 | 2 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 exome AF: 7.18e-7 AC: 1AN: 1393288Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 690378
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Spastic paraplegia Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 13, 2022 | 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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. ClinVar contains an entry for this variant (Variation ID: 374759). This missense change has been observed in individual(s) with hereditary spastic paraplegia (PMID: 31135052). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 69 of the FA2H protein (p.His69Tyr). - |
Hereditary spastic paraplegia 35 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Jan 08, 2018 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jul 31, 2016 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at