Variant 20-13785069-A-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate

The NM_024120.5(NDUFAF5):c.1A>C(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000549 in 1,458,394 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 (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

NDUFAF5
NM_024120.5 start_lost

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 1.41

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:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PVS1

Start lost variant, no new inframe start found.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 20-13785069-A-C is Pathogenic according to our data. Variant chr20-13785069-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 2703746.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NDUFAF5	NM_024120.5 linkuse as main transcript	c.1A>C	p.Met1?	start_lost	1/11	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.1A>C	p.Met1?	start_lost	1/11	1	NM_024120.5	ENSP00000367346	P1	Q5TEU4-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000164

AC:

AN:

243694

Hom.:

AF XY:

0.00000752

AC XY:

AN XY:

132966

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000117

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000549

AC:

AN:

1458394

Hom.:

Cov.:

AF XY:

0.00000551

AC XY:

AN XY:

725460

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000157

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:

9.00e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000434

Hom.:

Bravo

AF:

0.0000151

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 24, 2023

This sequence change affects the initiator methionine of the NDUFAF5 mRNA. The next in-frame methionine is located at codon 188. This variant is present in population databases (no rsID available, gnomAD 0.01%). Disruption of the initiator codon has been observed in individual(s) with mitochondrial complex I deficiency (PMID: 35379322). This variant disrupts a region of the NDUFAF5 protein in which other variant(s) (p.Lys109Asn) have been determined to be pathogenic (PMID: 30473481). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.20

BayesDel_noAF

Pathogenic

0.28

CADD

Benign

DANN

Benign

0.87

DEOGEN2

Benign

0.021

T;.

Eigen

Benign

-0.27

Eigen_PC

Benign

-0.20

FATHMM_MKL

Uncertain

0.80

LIST_S2

Uncertain

0.90

D;D

M_CAP

Pathogenic

0.57

MetaRNN

Pathogenic

0.94

D;D

MetaSVM

Benign

-0.62

MutationTaster

Benign

1.0

D;D

PROVEAN

Benign

-0.38

N;N

REVEL

Uncertain

0.45

Sift

Pathogenic

0.0

D;D

Sift4G

Benign

0.90

T;T

Polyphen

0.031

B;B

Vest4

0.52

MutPred

0.97

Gain of helix (P = 0.0199);Gain of helix (P = 0.0199);

MVP

0.73

ClinPred

0.86

GERP RS

4.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.96

gMVP

0.55

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