rs137852863

Positions:

chr5-61073136-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_174889.5(NDUFAF2):c.139C>T(p.Arg47Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000367 in 1,609,134 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000037 ( 0 hom. )

Consequence

NDUFAF2
NM_174889.5 stop_gained

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 0.860

Variant links:

Genes affected

NDUFAF2 (HGNC:28086): (NADH:ubiquinone oxidoreductase complex assembly factor 2) NADH:ubiquinone oxidoreductase (complex I) catalyzes the transfer of electrons from NADH to ubiquinone (coenzyme Q) in the first step of the mitochondrial respiratory chain, resulting in the translocation of protons across the inner mitochondrial membrane. This gene encodes a complex I assembly factor. Mutations in this gene cause progressive encephalopathy resulting from mitochondrial complex I deficiency. [provided by RefSeq, Jul 2008]

NDUFAF2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 5-61073136-C-T is Pathogenic according to our data. Variant chr5-61073136-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1594.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-61073136-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NDUFAF2	NM_174889.5 linkuse as main transcript	c.139C>T	p.Arg47Ter	stop_gained	2/4	ENST00000296597.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NDUFAF2	ENST00000296597.10 linkuse as main transcript	c.139C>T	p.Arg47Ter	stop_gained	2/4	1	NM_174889.5	P1

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

151952

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000399

AC:

AN:

250892

Hom.:

AF XY:

0.0000295

AC XY:

AN XY:

135656

show subpopulations

Gnomad AFR exome

AF:

0.0000617

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000272

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000353

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000371

AC:

AN:

1457182

Hom.:

Cov.:

AF XY:

0.0000359

AC XY:

AN XY:

725220

show subpopulations

Gnomad4 AFR exome

AF:

0.0000300

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000152

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000424

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000329

AC:

AN:

151952

Hom.:

Cov.:

AF XY:

0.0000270

AC XY:

AN XY:

74192

show subpopulations

Gnomad4 AFR

AF:

0.0000242

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000844

Hom.:

Bravo

AF:

0.0000604

ExAC

AF:

0.0000330

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 16, 2022	Published functional studies demonstrate that this variant causes a severe reduction in complex I activity and levels of holoenzyme (Ogilvie et al., 2005); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Also denoted as R45X due to alternate nomenclature; This variant is associated with the following publications: (PMID: 25525159, 25326635, 16200211, 10649489, 26795593, 31130284, 34503567) -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 22, 2024	This sequence change creates a premature translational stop signal (p.Arg47*) in the NDUFAF2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in NDUFAF2 are known to be pathogenic (PMID: 18180188). This variant is present in population databases (rs137852863, gnomAD 0.03%). This premature translational stop signal has been observed in individual(s) with clinical features of NDUFAF2-related conditions (PMID: 16200211, 31130284). This variant is also known as R45X. ClinVar contains an entry for this variant (Variation ID: 1594). For these reasons, this variant has been classified as Pathogenic. -

not specified

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Feb 08, 2018

Variant summary: NDUFAF2 c.139C>T (p.Arg47X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g., p.Trp74X). The variant allele was found at a frequency of 4.3e-05 in 276654 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in NDUFAF2 causing Leigh Syndrome (4.3e-05 vs 0.0013), allowing no conclusion about variant significance. The c.139C>T variant has been reported in the literature in multiple individuals affected with Leigh Syndrome. This data indicates that the variant may be associated with disease. At least one publication reports experimental evidence showing a lack of mature protein and no catalytic activity of the mitochondrial complex I (Ogilvie_2005). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic. -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 08, 2014

The c.139C>T (p.R47*) alteration, located in coding exon 2 (c.128_217) of the NDUFAF2 gene, consists of a C to T substitution at nucleotide position 139. This changes the amino acid from an Arginine (R) to a stop codon within coding exon 2 (c.128_217). Premature stop codons are typically deleterious in nature (Richards, 2008). The alteration has been observed in affected individuals: _x000D_ Homozygous c.139C>T (p.R47*) alterations have been reported in a non-consanguineous female patient of Chinese, Portuguese, and Jewish descent with complex I deficiency and clinical features overlapping with the proband including respiratory failure, global developmental delays, and brain MRI findings consistent with Leigh syndrome (Ogilvie, 2005). Based on the available evidence, this alteration is classified as pathogenic. -

Mitochondrial complex I deficiency, nuclear type 1

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Sep 17, 2018

The NDUFAF2 c.139C>T (p.Arg47Ter) variant, also known as c.182C>T (p.Arg45Ter), is a stop-gained variant predicted to result in premature termination of the protein. The variant has been reported in two studies in which it is found in two individuals. Ogilvie et al. (2005) reported a proband with an atypical phenotype of leukoencephalopathy with vanishing white matter, who was a hemizygote for the c.139C>T (p.Arg47Ter) variant. The proband inherited the p.Arg47Ter variant from her unaffected mother, and inherited a deletion variant from her unaffected father. Helbig et al. (2016) identified the p.Arg47Ter variant in a homozygous state in one proband with epileptic encephalopathy. Control data are unavailable for the p.Arg47Ter variant, which is reported at a frequency of 0.000265 in the East Asian population of the Genome Aggregation Database. Functional studies in proband fibroblasts demonstrated that wildtype NDUFAF2 transduction restored the complex I deficiency and activity to control levels, indicating the p.Arg47Ter variant was responsible for the proband's phenotype (Ogilvie et al. 2005). Based on the evidence, the p.Arg47Ter variant is classified as likely pathogenic for mitochondrial respiratory chain complex I deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Leigh syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Sep 01, 2017

This variant has been previously reported as disease-causing and was found once in our laboratory homozygous in a 4-month-old female with cutis marmorata telangiectasia congenita, onset of nystagmus and poor suck at 3.5 months, normal MRI, but with a brother deceased from Leigh syndrome with similar symptom onset -

Mitochondrial complex 1 deficiency, nuclear type 10

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 01, 2005

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.42

BayesDel_noAF

Pathogenic

0.55

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Uncertain

0.56

Eigen_PC

Uncertain

0.39

FATHMM_MKL

Uncertain

0.84

MutationTaster

Benign

1.0

A;A

Vest4

0.28

GERP RS

2.4

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