chr2-69396143-C-T
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Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBS1_Supporting
The NM_001002755.4(NFU1):c.*103G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000833 in 906,178 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.00063 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00087 ( 1 hom. )
Consequence
NFU1
NM_001002755.4 3_prime_UTR
NM_001002755.4 3_prime_UTR
Scores
2
Clinical Significance
Conservation
PhyloP100: 0.0880
Genes affected
NFU1 (HGNC:16287): (NFU1 iron-sulfur cluster scaffold) This gene encodes a protein that is localized to mitochondria and plays a critical role in iron-sulfur cluster biogenesis. The encoded protein assembles and transfers 4Fe-4S clusters to target apoproteins including succinate dehydrogenase and lipoic acid synthase. Mutations in this gene are a cause of multiple mitochondrial dysfunctions syndrome-1, and pseudogenes of this gene are located on the short arms of chromosomes 1 and 3. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Dec 2011]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -3 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.76).
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000631 (96/152088) while in subpopulation NFE AF= 0.00122 (83/68016). AF 95% confidence interval is 0.00101. There are 0 homozygotes in gnomad4. There are 50 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| NFU1 | NM_001002755.4 | c.*103G>A | 3_prime_UTR_variant | 8/8 | ENST00000410022.7 | NP_001002755.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| NFU1 | ENST00000410022.7 | c.*103G>A | 3_prime_UTR_variant | 8/8 | 1 | NM_001002755.4 | ENSP00000387219 | A1 |
Frequencies
GnomAD3 genomes 0.000631 AC: 96AN: 152088Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.000458 AC: 97AN: 211690Hom.: 0 AF XY: 0.000406 AC XY: 47AN XY: 115624
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GnomAD4 exome AF: 0.000874 AC: 659AN: 754090Hom.: 1 Cov.: 10 AF XY: 0.000796 AC XY: 319AN XY: 400778
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GnomAD4 genome 0.000631 AC: 96AN: 152088Hom.: 0 Cov.: 33 AF XY: 0.000673 AC XY: 50AN XY: 74294
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Multiple mitochondrial dysfunctions syndrome 1 Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
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