rs374514431
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Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong
The NM_001002755.4(NFU1):c.622G>T(p.Gly208Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000675 in 1,613,872 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 Pathogenic (★★).
Frequency
Genomes: 𝑓 0.00012 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000062 ( 0 hom. )
Consequence
NFU1
NM_001002755.4 missense
NM_001002755.4 missense
Scores
17
1
1
Clinical Significance
Conservation
PhyloP100: 7.38
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 Pathogenic. Variant got 16 ACMG points.
PM1
?
In a region_of_interest NifU (size 68) in uniprot entity NFU1_HUMAN there are 8 pathogenic changes around while only 0 benign (100%) in NM_001002755.4
PM2
?
Very rare variant in population databases, with high coverage;
PP3
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MetaRNN computational evidence supports a deleterious effect, 0.943
PP5
?
Variant 2-69400462-C-A is Pathogenic according to our data. Variant chr2-69400462-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 30700.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-69400462-C-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NFU1 | NM_001002755.4 | c.622G>T | p.Gly208Cys | missense_variant | 7/8 | ENST00000410022.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NFU1 | ENST00000410022.7 | c.622G>T | p.Gly208Cys | missense_variant | 7/8 | 1 | NM_001002755.4 | A1 |
Frequencies
GnomAD3 genomes ? AF: 0.000118 AC: 18AN: 152088Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000147 AC: 37AN: 251458Hom.: 0 AF XY: 0.000110 AC XY: 15AN XY: 135902
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GnomAD4 exome AF: 0.0000623 AC: 91AN: 1461784Hom.: 0 Cov.: 31 AF XY: 0.0000550 AC XY: 40AN XY: 727190
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:9
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Multiple mitochondrial dysfunctions syndrome 1 Pathogenic:5
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jan 22, 2023 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Nov 11, 2011 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego | May 14, 2020 | This variant has been previously reported as a compound heterozygous and homozygous change in patients with mitochondrial disease and cystic leukoencephalopathy (PMID: 22077971, 24462778, 28803783, 29441221). Functional studies showed absence of protein-bound lipoic acid in fibroblasts from individuals with this variant in the homozygous and compound heterozygous state, and decreased levels of lipoic acid in muscle biopsies from these individuals (PMID: 22077971, 23179554). It is present in the heterozygous state in the gnomAD population database at a frequency of .013% (38/282860) and thus is presumed to be rare. The c.622G>T (p.Gly208Cys) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.622G>T (p.Gly208Cys) variant is classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | May 01, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 11, 2023 | This sequence change replaces glycine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 208 of the NFU1 protein (p.Gly208Cys). This variant is present in population databases (rs374514431, gnomAD 0.08%). This missense change has been observed in individual(s) with clinical features of multiple mitochondrial dysfunctions syndrome (PMID: 22077971, 28803783, 29441221, 31970900). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 30700). 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 NFU1 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects NFU1 function (PMID: 22077971, 28161430, 31461310). For these reasons, this variant has been classified as Pathogenic. - |
not provided Pathogenic:3
Pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Feb 16, 2022 | In vitro functional studies in yeast showed that NFU1 protein with the G208C variant is functionally impaired (Navarro-Sastre et al., 2011), and protein expression profiles were impaired in fibroblasts from patients who are homozygous or compound heterozygous for the G208C variant (Ferrer-Corts et al., 2013).; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28161430, 24462778, 23179554, 22077971, 28803783, 29019354, 28906593, 25918518, 29441221, 31970900, 31589614) - |
Pathogenic, no assertion criteria provided | clinical testing | Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | - | - - |
NFU1-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jan 25, 2023 | The NFU1 c.622G>T variant is predicted to result in the amino acid substitution p.Gly208Cys. This variant has been reported in the homozygous and compound heterozygous states in patients with multiple mitochondrial dysfunctions syndrome 1 (Navarro-Sastre et al. 2011. PubMed ID: 22077971; Lebigot et al. 2017. PubMed ID: 28803783). In vitro functional studies suggest that this variant impairs the transfer of Fe-S clusters to target apoproteins, and causes defects in the lipoic acid biosynthesis and complex II pathways (Ferrer-Cortès et al. 2013. PubMed ID: 23179554; Lebigot et al. 2017. PubMed ID: 28803783; Wachnowsky et al. 2017. PubMed ID: 28161430). This variant is reported in 0.085% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-69627594-C-A). This variant is interpreted as pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Pathogenic
D;.;.;.;D;D
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D;D;D;.;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
H;.;.;.;.;.
MutationTaster
Benign
D;D;D;D
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D;D;D;D;D;D
REVEL
Pathogenic
Sift
Pathogenic
D;D;D;D;D;D
Sift4G
Pathogenic
D;D;D;D;.;D
Polyphen
D;.;D;.;.;.
Vest4
MVP
MPC
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
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