rs878855082
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Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PM4_Supporting
The NM_024306.5(FA2H):c.75_77delCTG(p.Cys25del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.0000114 in 1,399,232 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000011 ( 0 hom. )
Consequence
FA2H
NM_024306.5 disruptive_inframe_deletion
NM_024306.5 disruptive_inframe_deletion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 4.25
Genes affected
FA2H (HGNC:21197): (fatty acid 2-hydroxylase) This gene encodes a protein that catalyzes the synthesis of 2-hydroxysphingolipids, a subset of sphingolipids that contain 2-hydroxy fatty acids. Sphingolipids play roles in many cellular processes and their structural diversity arises from modification of the hydrophobic ceramide moiety, such as by 2-hydroxylation of the N-acyl chain, and the existence of many different head groups. Mutations in this gene have been associated with leukodystrophy dysmyelinating with spastic paraparesis with or without dystonia.[provided by RefSeq, Mar 2010]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 3 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PM4
Nonframeshift variant in NON repetitive region in NM_024306.5. Strenght limited to Supporting due to length of the change: 1aa.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
FA2H | ENST00000219368.8 | c.75_77delCTG | p.Cys25del | disruptive_inframe_deletion | 1/7 | 1 | NM_024306.5 | ENSP00000219368.3 | ||
FA2H | ENST00000567683.5 | n.75_77delCTG | non_coding_transcript_exon_variant | 1/5 | 2 | ENSP00000455126.1 |
Frequencies
GnomAD3 genomes AF: 0.0000132 AC: 2AN: 152036Hom.: 0 Cov.: 33
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GnomAD4 exome AF: 0.0000112 AC: 14AN: 1247196Hom.: 0 AF XY: 0.0000115 AC XY: 7AN XY: 611350
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GnomAD4 genome AF: 0.0000132 AC: 2AN: 152036Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74278
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Spastic paraplegia Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 08, 2024 | This variant, c.75_77del, results in the deletion of 1 amino acid(s) of the FA2H protein (p.Cys25del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with clinical features of hereditary spastic paraplegia (Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 241465). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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. - |
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at