rs4453725

chr2-69431994-A-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 8P and 16B. PVS1 BP6_Very_Strong BA1

The ENST00000303698.7(NFU1):c.2T>A(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.4 in 1,603,608 control chromosomes in the GnomAD database, including 131,872 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.37 (10993 hom., cov: 32)
  • Exomes 𝑓: 0.40 (120879 hom.)
• Consequence: NFU1 ENST00000303698.7 start_lost
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.886

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 Benign. Variant got -8 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• BP6: Variant 2-69431994-A-T is Benign according to our data. Variant chr2-69431994-A-T is described in ClinVar as [Benign]. Clinvar id is 138516.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-69431994-A-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.417 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NFU1	NM_001002755.4	c.74T>A	p.Met25Lys	missense_variant	2/8	ENST00000410022.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NFU1	ENST00000410022.7	c.74T>A	p.Met25Lys	missense_variant	2/8	1	NM_001002755.4	A1

Frequencies

GnomAD3 genomes AF: 0.372 AC: 56571 AN: 151946 Hom.: 10981 Cov.: 32

Gnomad AFR AF: 0.281

Gnomad AMI AF: 0.492

Gnomad AMR AF: 0.397

Gnomad ASJ AF: 0.533

Gnomad EAS AF: 0.200

Gnomad SAS AF: 0.369

Gnomad FIN AF: 0.397

Gnomad MID AF: 0.449

Gnomad NFE AF: 0.421

Gnomad OTH AF: 0.392

GnomAD3 exomes AF: 0.393 AC: 98476 AN: 250802 Hom.: 20057 AF XY: 0.395 AC XY: 53494 AN XY: 135596

Gnomad AFR exome AF: 0.278

Gnomad AMR exome AF: 0.393

Gnomad ASJ exome AF: 0.554

Gnomad EAS exome AF: 0.215

Gnomad SAS exome AF: 0.358

Gnomad FIN exome AF: 0.410

Gnomad NFE exome AF: 0.428

Gnomad OTH exome AF: 0.420

GnomAD4 exome AF: 0.403 AC: 585644 AN: 1451544 Hom.: 120879 Cov.: 30 AF XY: 0.403 AC XY: 291496 AN XY: 722826

Gnomad4 AFR exome AF: 0.266

Gnomad4 AMR exome AF: 0.394

Gnomad4 ASJ exome AF: 0.554

Gnomad4 EAS exome AF: 0.200

Gnomad4 SAS exome AF: 0.361

Gnomad4 FIN exome AF: 0.408

Gnomad4 NFE exome AF: 0.415

Gnomad4 OTH exome AF: 0.399

GnomAD4 genome AF: 0.372 AC: 56599 AN: 152064 Hom.: 10993 Cov.: 32 AF XY: 0.372 AC XY: 27643 AN XY: 74342

Gnomad4 AFR AF: 0.281

Gnomad4 AMR AF: 0.397

Gnomad4 ASJ AF: 0.533

Gnomad4 EAS AF: 0.200

Gnomad4 SAS AF: 0.368

Gnomad4 FIN AF: 0.397

Gnomad4 NFE AF: 0.421

Gnomad4 OTH AF: 0.399

Alfa AF: 0.425 Hom.: 4673

Bravo AF: 0.367

TwinsUK AF: 0.406 AC: 1504

ALSPAC AF: 0.417 AC: 1607

ESP6500AA AF: 0.280 AC: 1235

ESP6500EA AF: 0.427 AC: 3671

ExAC AF: 0.391 AC: 47490

Asia WGS AF: 0.311 AC: 1080 AN: 3476

EpiCase AF: 0.424

EpiControl AF: 0.432

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 05, 2013	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Multiple mitochondrial dysfunctions syndrome 1 Benign:3

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

not provided Benign:1

Benign, no assertion criteria provided

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

Feb 19, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.39
Cadd	Benign	7.5
Dann	Benign	0.85
DEOGEN2	Benign	0.025	T;.
Eigen	Benign	-0.93
Eigen_PC	Benign	-0.89
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.39	T;D
MetaRNN	Benign	0.00029	T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.55	N;.
MutationTaster	Benign	0.000045	P;P;P
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.55	N;N
REVEL	Benign	0.10
Sift	Benign	0.53	T;D
Sift4G	Benign	0.18	T;D
Polyphen		0.0070	B;B
Vest4		0.11
MPC		0.22
ClinPred		0.0029	T
GERP RS		3.9
Varity_R		0.084
gMVP		0.60

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: rs4453725; hg19: chr2-69659126; COSMIC: COSV58006358;