20-13816520-T-G

Position:

chr20-13816520-T-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PP3_ModeratePP5_Very_Strong

The NM_024120.5(NDUFAF5):c.836T>G(p.Met279Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000805 in 1,614,000 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 (★★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000068 ( 0 hom. )

Consequence

NDUFAF5
NM_024120.5 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6U:1

Conservation

PhyloP100: 6.72

Variant links:

Genes affected

NDUFAF5 (HGNC:15899): (NADH:ubiquinone oxidoreductase complex assembly factor 5) The NADH-ubiquinone oxidoreductase complex (complex I) of the mitochondrial respiratory chain catalyzes the transfer of electrons from NADH to ubiquinone, and consists of at least 43 subunits. The complex is located in the inner mitochondrial membrane. This gene encodes a mitochondrial protein that is associated with the matrix face of the mitochondrial inner membrane and is required for complex I assembly. A mutation in this gene results in mitochondrial complex I deficiency. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2009]

NDUFAF5 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.85

PP5

Variant 20-13816520-T-G is Pathogenic according to our data. Variant chr20-13816520-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 225036.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-13816520-T-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NDUFAF5	NM_024120.5 linkuse as main transcript	c.836T>G	p.Met279Arg	missense_variant	9/11	ENST00000378106.10	NP_077025.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NDUFAF5	ENST00000378106.10 linkuse as main transcript	c.836T>G	p.Met279Arg	missense_variant	9/11	1	NM_024120.5	ENSP00000367346	P1	Q5TEU4-1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152192

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000578

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000557

AC:

AN:

251314

Hom.:

AF XY:

0.0000294

AC XY:

AN XY:

135828

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000761

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000684

AC:

AN:

1461808

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

727214

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152192

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74364

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000578

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.0000412

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Mitochondrial complex 1 deficiency, nuclear type 16

Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 11, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Nov 24, 2023	- -

Leigh syndrome

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 24, 2022	Variant summary: NDUFAF5 c.836T>G (p.Met279Arg) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.6e-05 in 251314 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in NDUFAF5 causing Leigh Syndrome (5.6e-05 vs 0.00056), allowing no conclusion about variant significance. c.836T>G has been reported in the literature as homozygous and compound heterozygous genotypes in multiple well characterized and comprehensively sequenced (by WES) individuals of East Asian ancestry affected with heterogeneous phenotypes of mitochondrial complex 1 assembly gene deficiency such as Leigh Syndrome, neurodevelopmental delay accompanied by unexplained dyspnea, lactic acidosis and Bilateral striatal necrosis (BSN) (example, Farwell_2015, Tong_2018, Simon_2019, Bi_2021). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories and the OMIM database have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (Pathogenic/Likely Pathogenic, n=2; VUS, n=1). Based on the evidence outlined above, the variant was classified as pathogenic. -
Likely pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

Inborn genetic diseases

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 12, 2013

- -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 03, 2024

This sequence change replaces methionine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 279 of the NDUFAF5 protein (p.Met279Arg). This variant is present in population databases (rs761389904, gnomAD 0.09%). This missense change has been observed in individuals with mitochondrial complex I deficiency (PMID: 29581464, 30473481, 30581749, 34177781). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 225036). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on NDUFAF5 protein function. For these reasons, this variant has been classified as Pathogenic. -

Mitochondrial complex I deficiency

Uncertain:1

Uncertain significance, flagged submission

clinical testing

Baylor Genetics

Sep 01, 2017

Likely pathogenicity based on finding it once in our laboratory homozygous in a 13-year-old female with regression of motor skills, minor cognitive delays, hypotonia, restrictive lung disease, epilepsy, short stature, structural brain abnormalities, esotropia, hypertension -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.76

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Pathogenic

0.36

CADD

Pathogenic

DANN

Uncertain

0.98

DEOGEN2

Benign

0.29

T;.

Eigen

Uncertain

0.62

Eigen_PC

Uncertain

0.61

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Pathogenic

1.0

D;D

M_CAP

Uncertain

0.18

MetaRNN

Pathogenic

0.85

D;D

MetaSVM

Uncertain

0.41

MutationAssessor

Uncertain

2.8

M;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.63

PROVEAN

Uncertain

-4.3

D;D

REVEL

Pathogenic

0.89

Sift

Uncertain

0.0010

D;D

Sift4G

Uncertain

0.0020

D;D

Polyphen

0.93

P;D

Vest4

0.80

MutPred

0.81

Gain of methylation at M279 (P = 0.0042);.;

MVP

0.93

MPC

0.60

ClinPred

0.88

GERP RS

5.4

Varity_R

0.88

gMVP

0.95

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