rs374514431

Variant names:

• chr2-69400462-C-A
• rs374514431
• NM_001002755.4:c.622G>T
• NFU1 p.Gly208Cys

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PS3 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 (★★). ClinVar reports functional evidence for this variant: "SCV001984858: 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)." and additional evidence is available in ClinVar.

• 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
• Publications: 37 publications found

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]

NFU1 Gene-Disease associations (from GenCC):

• mitochondrial disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• multiple mitochondrial dysfunctions syndrome 1

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV001984858: 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).; SCV002243592: Experimental studies have shown that this missense change affects NFU1 function (PMID: 22077971, 28161430, 31461310).; SCV000329903: "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)."; SCV004115995: "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)."
• 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 VariationId is 30700.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001002755.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NFU1	NM_001002755.4	MANE Select	c.622G>T	p.Gly208Cys	missense	Exon 7 of 8	NP_001002755.1	Q9UMS0-1
	NFU1	NM_001374284.1		c.550G>T	p.Gly184Cys	missense	Exon 8 of 9	NP_001361213.1	Q9UMS0-3
	NFU1	NM_015700.4		c.550G>T	p.Gly184Cys	missense	Exon 7 of 8	NP_056515.2	Q9UMS0-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NFU1	ENST00000410022.7	TSL:1 MANE Select	c.622G>T	p.Gly208Cys	missense	Exon 7 of 8	ENSP00000387219.3	Q9UMS0-1
	NFU1	ENST00000303698.7	TSL:1	c.550G>T	p.Gly184Cys	missense	Exon 7 of 8	ENSP00000306965.3	Q9UMS0-3
	NFU1	ENST00000875857.1		c.622G>T	p.Gly208Cys	missense	Exon 7 of 9	ENSP00000545916.1

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

GnomAD2 exomes AF: 0.000147 AC: 37 AN: 251458 AF XY: 0.000110

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 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

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.000715 AC: 32 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39692

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000486 AC: 54 AN: 1111920

Other (OTH) AF: 0.0000662 AC: 4 AN: 60392

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

African (AFR) AF: 0.00 AC: 0 AN: 41408

American (AMR) AF: 0.000590 AC: 9 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10590

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 68022

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.0000576 Hom.: 0

Bravo AF: 0.000174

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
5	-	-	Multiple mitochondrial dysfunctions syndrome 1 (5)
3	-	-	not provided (3)
1	-	-	NFU1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.96
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.53	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	5.2	H
PhyloP100		7.4
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-8.8	D
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.98
gMVP		0.96
Mutation Taster		=3/97	disease causing (ClinVar)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs374514431;

hg19: chr2-69627594;