rs757043077

chr20-13808873-G-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2 PP5_Very_Strong

The NM_024120.5(NDUFAF5):c.749G>T(p.Gly250Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000163 in 1,596,388 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. G250G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000017 (0 hom.)
• Consequence: NDUFAF5 NM_024120.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 8.91

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]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 20-13808873-G-T is Pathogenic according to our data. Variant chr20-13808873-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 372253.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-13808873-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NDUFAF5	NM_024120.5	c.749G>T	p.Gly250Val	missense_variant	8/11	ENST00000378106.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NDUFAF5	ENST00000378106.10	c.749G>T	p.Gly250Val	missense_variant	8/11	1	NM_024120.5	P1

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 152006 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

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: 0.0000438 AC: 11 AN: 250970 Hom.: 0 AF XY: 0.0000369 AC XY: 5 AN XY: 135682

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00109

Gnomad EAS exome AF: 0.00

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: 0.0000166 AC: 24 AN: 1444382 Hom.: 0 Cov.: 27 AF XY: 0.0000236 AC XY: 17 AN XY: 719864

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.000807

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000182

Gnomad4 OTH exome AF: 0.0000167

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 152006 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74224

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000130 Hom.: 0

Bravo AF: 0.0000302

ExAC AF: 0.0000412 AC: 5

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Mitochondrial complex 1 deficiency, nuclear type 16 Pathogenic:3

Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 06, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jul 01, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 04, 2023	- -

not provided Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 11, 2023	Observed with another NDUFAF5 variant on the opposite allele (in trans) in a patient features of NDUFAF5-related disorder in published literature (Simon et al., 2019); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 22664328, 22099533, 21607760, 21924235, 23536703, 30581749, 30473481, 34964562, 34177781) -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Oct 08, 2021	This variant segregates with disease in multiple families and is considered a founder variant among individuals of Ashkenazi Jewish ancestry (PMID: 21607760). The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). Computational tools yielded predictions that this amino acid change may be damaging to the protein.This observation is not an independent occurrence and has been identified in the same individual by RCIGM, the other laboratory participating in the GEMINI study. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 21, 2024	This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 250 of the NDUFAF5 protein (p.Gly250Val). This variant is present in population databases (rs757043077, gnomAD 0.1%). This missense change has been observed in individuals with mitochondrial complex I deficiency (PMID: 21607760). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 372253). 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 Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

Division of Human Genetics, Children's Hospital of Philadelphia

Jan 15, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.66
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.30
Cadd	Pathogenic	33
Dann	Uncertain	1.0
DEOGEN2	Benign	0.26	T;.
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Benign	0.061	D
MetaRNN	Uncertain	0.74	D;D
MetaSVM	Uncertain	-0.033	T
MutationAssessor	Uncertain	2.7	M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-3.2	D;D
REVEL	Pathogenic	0.75
Sift	Uncertain	0.018	D;D
Sift4G	Uncertain	0.021	D;D
Polyphen		0.98	D;D
Vest4		0.97
MutPred		0.65		Loss of sheet (P = 0.0126);.;
MVP		0.93
MPC		0.57
ClinPred		0.94	D
GERP RS		5.5
Varity_R		0.60
gMVP		0.88

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

Other links and lift over

dbSNP: rs757043077; hg19: chr20-13789519;