rs4453725

Positions:

chr2-69431994-A-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 8P and 16B. PVS1BP6_Very_StrongBA1

The NM_015700.4(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
NM_015700.4 start_lost

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 0.886

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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	Protein	UniProt
NFU1	NM_001002755.4 link	c.74T>A	p.Met25Lys	missense_variant	2/8	ENST00000410022.7	NP_001002755.1	Q9UMS0-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NFU1	ENST00000410022.7 link	c.74T>A	p.Met25Lys	missense_variant	2/8	1	NM_001002755.4	ENSP00000387219.3		Q9UMS0-1

Frequencies

GnomAD3 genomes

AF:

0.372

AC:

56571

AN:

151946

Hom.:

10981

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.403

AC XY:

291496

AN XY:

722826

show subpopulations

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.:

AF XY:

0.372

AC XY:

27643

AN XY:

74342

show subpopulations

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:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

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	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
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	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Multiple mitochondrial dysfunctions syndrome 1

Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
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. -

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
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

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

LIST_S2

Benign

0.39

T;D

MetaRNN

Benign

0.00029

T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.55

N;.

PrimateAI

Benign

0.42

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over