rs75711361
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Variant summary
Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2
The NM_024306.5(FA2H):c.537G>A(p.Leu179=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000848 in 1,613,956 control chromosomes in the GnomAD database, including 27 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Genomes: 𝑓 0.0010 ( 4 hom., cov: 33)
Exomes 𝑓: 0.00083 ( 23 hom. )
Consequence
FA2H
NM_024306.5 synonymous
NM_024306.5 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: 0.434
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 Benign. Variant got -19 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.32).
BP6
?
Variant 16-74726301-C-T is Benign according to our data. Variant chr16-74726301-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 320498.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-74726301-C-T is described in Lovd as [Likely_benign]. Variant chr16-74726301-C-T is described in Lovd as [Benign].
BP7
?
Synonymous conserved (PhyloP=0.434 with no splicing effect.
BS1
?
Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00102 (156/152280) while in subpopulation EAS AF= 0.0288 (149/5178). AF 95% confidence interval is 0.025. There are 4 homozygotes in gnomad4. There are 96 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
?
High Homozygotes in GnomAd4 at 4 AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FA2H | NM_024306.5 | c.537G>A | p.Leu179= | synonymous_variant | 4/7 | ENST00000219368.8 | |
FA2H | XM_011523317.4 | c.537G>A | p.Leu179= | synonymous_variant | 4/6 | ||
FA2H | XM_011523319.3 | c.297G>A | p.Leu99= | synonymous_variant | 4/7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FA2H | ENST00000219368.8 | c.537G>A | p.Leu179= | synonymous_variant | 4/7 | 1 | NM_024306.5 | P1 | |
FA2H | ENST00000569949.1 | c.339G>A | p.Leu113= | synonymous_variant | 4/5 | 4 | |||
FA2H | ENST00000567683.5 | c.364-7141G>A | intron_variant, NMD_transcript_variant | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.00103 AC: 157AN: 152162Hom.: 4 Cov.: 33
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GnomAD3 exomes AF: 0.00233 AC: 585AN: 250708Hom.: 12 AF XY: 0.00221 AC XY: 299AN XY: 135450
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GnomAD4 exome AF: 0.000829 AC: 1212AN: 1461676Hom.: 23 Cov.: 30 AF XY: 0.000824 AC XY: 599AN XY: 727142
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GnomAD4 genome ? AF: 0.00102 AC: 156AN: 152280Hom.: 4 Cov.: 33 AF XY: 0.00129 AC XY: 96AN XY: 74450
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Benign:3
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Feb 09, 2021 | - - |
Likely benign, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Benign, criteria provided, single submitter | clinical testing | Athena Diagnostics | Jun 29, 2018 | - - |
Spastic paraplegia Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 20, 2024 | - - |
not specified Benign:1
Benign, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Hereditary spastic paraplegia 35 Benign:1
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. - |
Hereditary spastic paraplegia Benign:1
Benign, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, The Hospital for Sick Children | Jun 13, 2021 | - - |
Computational scores
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at