2-69396278-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_001002755.4(NFU1):c.733G>A(p.Glu245Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000311 in 1,609,932 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: NFU1 NM_001002755.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.67

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 Uncertain_significance. Variant got 2 ACMG points.

• PM1: In a chain NFU1 iron-sulfur cluster scaffold homolog, mitochondrial (size 244) in uniprot entity NFU1_HUMAN there are 9 pathogenic changes around while only 1 benign (90%) in NM_001002755.4
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20922878).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NFU1	NM_001002755.4	c.733G>A	p.Glu245Lys	missense_variant	8/8	ENST00000410022.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NFU1	ENST00000410022.7	c.733G>A	p.Glu245Lys	missense_variant	8/8	1	NM_001002755.4	A1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152160 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

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: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000120 AC: 3 AN: 249958 Hom.: 0 AF XY: 0.0000148 AC XY: 2 AN XY: 135058

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000873

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1457772 Hom.: 0 Cov.: 28 AF XY: 0.00000276 AC XY: 2 AN XY: 725344

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000673

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.01e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152160 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74324

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Multiple mitochondrial dysfunctions syndrome 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 10, 2023

An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 245 of the NFU1 protein (p.Glu245Lys). This variant is present in population databases (no rsID available, gnomAD 0.009%). This variant has not been reported in the literature in individuals affected with NFU1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1905628). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.080	T
BayesDel_noAF	Benign	-0.15
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.033	T;.;.;.
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.91	D;D;D;.
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.21	T;T;T;T
MetaSVM	Uncertain	-0.25	T
MutationAssessor	Uncertain	2.5	M;.;.;.
MutationTaster	Benign	0.99	D;D;D;D
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-0.92	N;N;N;N
REVEL	Benign	0.28
Sift	Uncertain	0.0030	D;D;D;D
Sift4G	Uncertain	0.051	T;D;D;D
Polyphen		0.45	B;.;.;.
Vest4		0.18
MutPred		0.35		Gain of ubiquitination at E245 (P = 9e-04);.;.;.;
MVP		0.81
MPC		0.16
ClinPred		0.59	D
GERP RS		5.3
Varity_R		0.20
gMVP		0.55

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1396495424; hg19: chr2-69623410;