chr20-13785071-G-A

Variant names:

• chr20-13785071-G-A
• NM_024120.5:c.3G>A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_Moderate PM2 PP5_Moderate

The NM_024120.5(NDUFAF5):​c.3G>A​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: NDUFAF5 NM_024120.5 start_lost
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 1.53

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]

ESF1 (HGNC:15898): (ESF1 nucleolar pre-rRNA processing protein homolog) Enables RNA binding activity. Predicted to be involved in rRNA processing. Located in extracellular space. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 2 pathogenic variants. Next in-frame start position is after 188 codons. Genomic position: 13801528. Lost 0.541 part of the original CDS.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 20-13785071-G-A is Pathogenic according to our data. Variant chr20-13785071-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 2797761.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NDUFAF5	NM_024120.5	c.3G>A	p.Met1?	start_lost	Exon 1 of 11	ENST00000378106.10	NP_077025.2
ESF1	NM_001276380.2	c.-235C>T		upstream_gene_variant		ENST00000617257.2	NP_001263309.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NDUFAF5	ENST00000378106.10	c.3G>A	p.Met1?	start_lost	Exon 1 of 11	1	NM_024120.5	ENSP00000367346.5
ESF1	ENST00000617257.2	c.-235C>T		upstream_gene_variant		5	NM_001276380.2	ENSP00000480783.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Apr 05, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. 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. Disruption of the initiator codon has been observed in individual(s) with mitochondrial complex I deficiency (PMID: 35379322). This variant is not present in population databases (gnomAD no frequency). This sequence change affects the initiator methionine of the NDUFAF5 mRNA. The next in-frame methionine is located at codon 188. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.026	T;.
Eigen	Benign	-0.20
Eigen_PC	Benign	-0.10
FATHMM_MKL	Benign	0.58	D
LIST_S2	Uncertain	0.90	D;D
M_CAP	Pathogenic	0.53	D
MetaRNN	Pathogenic	0.96	D;D
MetaSVM	Benign	-0.58	T
PROVEAN	Benign	-0.83	N;N
REVEL	Uncertain	0.41
Sift	Pathogenic	0.0	D;D
Sift4G	Benign	0.074	T;T
Polyphen		0.013	B;B
Vest4		0.66
MutPred		0.98		Gain of catalytic residue at M1 (P = 0.0179);Gain of catalytic residue at M1 (P = 0.0179);
MVP		0.70
ClinPred		0.98	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.6
Varity_R		0.96
gMVP		0.60

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr20-13765717;