2-69400462-C-A

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_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
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:9
• 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]

ACMG classification

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: 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: 18 AN: 152088 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000590

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000147 AC: 37 AN: 251458 Hom.: 0 AF XY: 0.000110 AC XY: 15 AN XY: 135902

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000838

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000703

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000623 AC: 91 AN: 1461784 Hom.: 0 Cov.: 31 AF XY: 0.0000550 AC XY: 40 AN XY: 727190

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000715

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000486

Gnomad4 OTH exome AF: 0.0000662

GnomAD4 genome AF: 0.000118 AC: 18 AN: 152088 Hom.: 0 Cov.: 32 AF XY: 0.000121 AC XY: 9 AN XY: 74298

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000590

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000680 Hom.: 0

Bravo AF: 0.000174

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000123 AC: 15

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Multiple mitochondrial dysfunctions syndrome 1 Pathogenic:5

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, no assertion criteria provided	literature only	OMIM	Nov 11, 2011	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jan 22, 2023	- -
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. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	May 01, 2021	- -

not provided Pathogenic:3

Pathogenic, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
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	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

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: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.55
Cadd	Pathogenic	33
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.84	D;.;.;.;D;D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.96
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D;D;D;.;D;D
M_CAP	Pathogenic	0.53	D
MetaRNN	Pathogenic	0.94	D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	5.2	H;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-8.8	D;D;D;D;D;D
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D;D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;.;D
Polyphen		1.0	D;.;D;.;.;.
Vest4		0.96
MVP		0.98
MPC		0.64
ClinPred		0.99	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.98
gMVP		0.96

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs374514431; hg19: chr2-69627594;