NM_001002755.4:c.411T>C

Variant names:

• chr2-69415258-A-G
• rs12474866
• NM_001002755.4:c.411T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001002755.4(NFU1):​c.411T>C​(p.Ile137Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0048 in 1,612,638 control chromosomes in the GnomAD database, including 541 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0097 (84 hom., cov: 32)
  • Exomes 𝑓: 0.0043 (457 hom.)
• Consequence: NFU1 NM_001002755.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.439
• Publications: 1 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant 2-69415258-A-G is Benign according to our data. Variant chr2-69415258-A-G is described in ClinVar as Benign. ClinVar VariationId is 138515.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.439 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.082 is higher than 0.05.

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.411T>C	p.Ile137Ile	synonymous	Exon 5 of 8	NP_001002755.1	Q9UMS0-1
	NFU1	NM_001374284.1		c.339T>C	p.Ile113Ile	synonymous	Exon 6 of 9	NP_001361213.1	Q9UMS0-3
	NFU1	NM_015700.4		c.339T>C	p.Ile113Ile	synonymous	Exon 5 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.411T>C	p.Ile137Ile	synonymous	Exon 5 of 8	ENSP00000387219.3	Q9UMS0-1
	NFU1	ENST00000303698.7	TSL:1	c.339T>C	p.Ile113Ile	synonymous	Exon 5 of 8	ENSP00000306965.3	Q9UMS0-3
	NFU1	ENST00000875857.1		c.411T>C	p.Ile137Ile	synonymous	Exon 5 of 9	ENSP00000545916.1

Frequencies

GnomAD3 genomes AF: 0.00976 AC: 1486 AN: 152190 Hom.: 84 Cov.: 32

Gnomad AFR AF: 0.00297

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0861

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.0163

GnomAD2 exomes AF: 0.0196 AC: 4915 AN: 251278 AF XY: 0.0144

Gnomad AFR exome AF: 0.00215

Gnomad AMR exome AF: 0.138

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000326

Gnomad FIN exome AF: 0.000462

Gnomad NFE exome AF: 0.0000528

Gnomad OTH exome AF: 0.0130

GnomAD4 exome AF: 0.00428 AC: 6257 AN: 1460330 Hom.: 457 Cov.: 29 AF XY: 0.00351 AC XY: 2551 AN XY: 726620

African (AFR) AF: 0.00161 AC: 54 AN: 33448

American (AMR) AF: 0.129 AC: 5780 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26116

East Asian (EAS) AF: 0.000328 AC: 13 AN: 39680

South Asian (SAS) AF: 0.000754 AC: 65 AN: 86202

European-Finnish (FIN) AF: 0.000843 AC: 45 AN: 53410

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5674

European-Non Finnish (NFE) AF: 0.0000405 AC: 45 AN: 1110762

Other (OTH) AF: 0.00423 AC: 255 AN: 60330

GnomAD4 genome AF: 0.00975 AC: 1485 AN: 152308 Hom.: 84 Cov.: 32 AF XY: 0.0106 AC XY: 788 AN XY: 74466

African (AFR) AF: 0.00296 AC: 123 AN: 41580

American (AMR) AF: 0.0859 AC: 1313 AN: 15288

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

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5188

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4824

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 68024

Other (OTH) AF: 0.0161 AC: 34 AN: 2114

Alfa AF: 0.00343 Hom.: 10

Bravo AF: 0.0179

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Multiple mitochondrial dysfunctions syndrome 1 (2)
-	-	1	NFU1-related disorder (1)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	9.4
DANN	Benign	0.79
PhyloP100		0.44
Mutation Taster		=285/15	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: rs12474866; hg19: chr2-69642390; COSMIC: COSV58006415;