dbSNP rs199754807: NDUFAF2:p.Tyr38* (chr5-60945369-C-G) – ACMG Classification: Pathogenic (18 pts)

Variant summary

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

The NM_174889.5(NDUFAF2):c.114C>G(p.Tyr38*) variant causes a stop gained change. The variant allele was found at a frequency of 0.000116 in 1,614,102 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 Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00013 ( 0 hom. )

Consequence

NDUFAF2
NM_174889.5 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:9U:1

Conservation

PhyloP100: 3.86

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 5-60945369-C-G is Pathogenic according to our data. Variant chr5-60945369-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 419231.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NDUFAF2	NM_174889.5 link	c.114C>G	p.Tyr38*	stop_gained	Exon 1 of 4	ENST00000296597.10	NP_777549.1	Q8N183A0A0S2Z5U1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NDUFAF2	ENST00000296597.10 link	c.114C>G	p.Tyr38*	stop_gained	Exon 1 of 4	1	NM_174889.5	ENSP00000296597.5		Q8N183

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000557

AC:

AN:

251384

Hom.:

AF XY:

0.0000736

AC XY:

AN XY:

135870

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000114

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000126

AC:

184

AN:

1461892

Hom.:

Cov.:

AF XY:

0.000125

AC XY:

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000162

Gnomad4 OTH exome

AF:

0.0000662

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152210

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74358

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000141

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.0000494

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Mitochondrial complex 1 deficiency, nuclear type 10

Pathogenic:4

Aug 28, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The NDUFAF2 c.114C>G; p.Tyr38Ter variant (rs199754807) is reported in the literature in a homozygous individual affected with mitochondrial complex I deficiency (Hoefs 2009). This variant is reported in ClinVar (Variation ID: 419231) and is found in the general population with an overall allele frequency of 0.005% (15/282,774 alleles) in the Genome Aggregation Database (v2.1.1). This variant induces an early termination codon and while mRNA studies of patient cells suggest this variant may escape nonsense-mediated decay, it is predicted to result in a truncated protein. Patient cells homozygous for this variant exhibit significantly decreased mitochondrial complex I activity (Hoefs 2009). Based on available information, this variant is considered to be pathogenic. References: Hoefs SJ et al. Baculovirus complementation restores a novel NDUFAF2 mutation causing complex I deficiency. Hum Mutat. 2009 Jul;30(7):E728-36. PMID: 19384974. -

Mar 18, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 13, 2018

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

May 21, 2020

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

A heterozygous nonsense variant, NM_174889.4(NDUFAF2):c.114C>G, has been identified in exon 1 of 4 of the NDUFAF2 gene. The variant is predicted to result in a premature stop codon at position 38 of the protein, NP_777549.1(NDUFAF2):p.(Tyr38*). This variant is predicted to result in loss of protein function through truncation (including the NDUFA12 domain), which is a reported mechanism of pathogenicity for this gene. The variant has been previously described as pathogenic and identified in a homozygous patient with complex I deficiency and clinical symptoms of Leigh disease (ClinVar, Hoefs, S. et al. (2009)). Additionally, functional studies showed a decrease in complex I activity in the cultured skin fibroblasts and a disturbance in the assembly of complex I (Hoefs, S. et al. (2009)). Other variants resulting in a truncated protein have been reported as pathogenic in this gene (ClinVar)). Based on the information available at the time of curation, this variant has been classified as PATHOGENIC. -

not provided

Pathogenic:2

May 26, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 19384974) -

May 20, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Tyr38*) 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 (rs199754807, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with mitochondrial complex I deficiency (PMID: 19384974). ClinVar contains an entry for this variant (Variation ID: 419231). For these reasons, this variant has been classified as Pathogenic. -

not specified

Pathogenic:1

Nov 21, 2018

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: NDUFAF2 c.114C>G (p.Tyr38X) 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 has been classified as pathogenic by our laboratory (e.g. c.139C>T, p.Arg47X; c.221G>A, p.Trp74X). The variant allele was found at a frequency of 5.4e-05 in 277122 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in NDUFAF2 causing Leigh Syndrome (5.4e-05 vs 0.0013), allowing no conclusion about variant significance. The variant, c.114C>G, has been reported in the literature in one homozygote individual affected with Leigh Syndrome (Hoefs_2009). These data indicate that the variant may be associated with disease. The same publication reports experimental evidence showing no NDUFAF2 protein expression in patient's fibroblasts and a marked decrease in complex I activity (to 21-23% of the lowest control value). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (pathogenic x2, VUS x1). Based on the evidence outlined above, the variant was classified as pathogenic. -

Mitochondrial complex I deficiency, nuclear type 1

Pathogenic:1

Dec 12, 2018

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported as disease causing [PMID 19384974] -

NDUFAF2-related disorder

Pathogenic:1

Apr 24, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The NDUFAF2 c.114C>G variant is predicted to result in premature protein termination (p.Tyr38*). This variant was reported in the homozygous state in an individual with mitochondrial complex I deficiency (Hoefs et al. 2009. PubMed ID: 19384974). This variant is reported in 0.010% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Nonsense variants in NDUFAF2 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Cockayne syndrome type 1

Uncertain:1

Apr 23, 2018

Counsyl

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.46

BayesDel_noAF

Pathogenic

0.57

CADD

Pathogenic

DANN

Uncertain

0.99

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.87

FATHMM_MKL

Uncertain

0.92

Vest4

0.20

ClinPred

0.98

GERP RS

5.4

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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