rs4453725

Variant names:

• chr2-69431994-A-T
• rs4453725
• ENST00000303698.7:c.2T>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 2P and 16B. PVS1_Moderate BP6_Very_Strong BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.886
• Publications: 29 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: Benign. The variant received -14 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 1 pathogenic variants. Next in-frame start position is after 35 codons. Genomic position: 69423709. Lost 0.149 part of the original CDS.
• BP6: Variant 2-69431994-A-T is Benign according to our data. Variant chr2-69431994-A-T is described in ClinVar as Benign. ClinVar VariationId is 138516.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.417 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015700.4. 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.74T>A	p.Met25Lys	missense	Exon 2 of 8	NP_001002755.1	Q9UMS0-1
	NFU1	NM_001374284.1		c.2T>A	p.Met1?	start_lost	Exon 3 of 9	NP_001361213.1	Q9UMS0-3
	NFU1	NM_015700.4		c.2T>A	p.Met1?	start_lost	Exon 2 of 8	NP_056515.2	Q9UMS0-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NFU1	ENST00000303698.7	TSL:1	c.2T>A	p.Met1?	start_lost	Exon 2 of 8	ENSP00000306965.3	Q9UMS0-3
	NFU1	ENST00000410022.7	TSL:1 MANE Select	c.74T>A	p.Met25Lys	missense	Exon 2 of 8	ENSP00000387219.3	Q9UMS0-1
	NFU1	ENST00000875857.1		c.74T>A	p.Met25Lys	missense	Exon 2 of 9	ENSP00000545916.1

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

GnomAD2 exomes AF: 0.393 AC: 98476 AN: 250802 AF XY: 0.395

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 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

African (AFR) AF: 0.266 AC: 8867 AN: 33276

American (AMR) AF: 0.394 AC: 17609 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.554 AC: 14437 AN: 26066

East Asian (EAS) AF: 0.200 AC: 7939 AN: 39620

South Asian (SAS) AF: 0.361 AC: 31088 AN: 86048

European-Finnish (FIN) AF: 0.408 AC: 21756 AN: 53316

Middle Eastern (MID) AF: 0.415 AC: 2384 AN: 5740

European-Non Finnish (NFE) AF: 0.415 AC: 457652 AN: 1102786

Other (OTH) AF: 0.399 AC: 23912 AN: 60002

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

African (AFR) AF: 0.281 AC: 11636 AN: 41476

American (AMR) AF: 0.397 AC: 6064 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.533 AC: 1852 AN: 3472

East Asian (EAS) AF: 0.200 AC: 1038 AN: 5180

South Asian (SAS) AF: 0.368 AC: 1772 AN: 4818

European-Finnish (FIN) AF: 0.397 AC: 4198 AN: 10572

Middle Eastern (MID) AF: 0.446 AC: 131 AN: 294

European-Non Finnish (NFE) AF: 0.421 AC: 28618 AN: 67958

Other (OTH) AF: 0.399 AC: 841 AN: 2108

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	Multiple mitochondrial dysfunctions syndrome 1 (3)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

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
MetaRNN	Benign	0.00029	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.55	N
PhyloP100		0.89
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.55	N
REVEL	Benign	0.10
Sift	Benign	0.53	T
Sift4G	Benign	0.18	T
Polyphen		0.0070	B
Vest4		0.11
MPC		0.22
ClinPred		0.0029	T
GERP RS		3.9
Varity_R		0.084
gMVP		0.60
Mutation Taster		=159/41	polymorphism (auto)

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

Other links and lift over

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