chr20-13785077-G-GC

Variant names:

• chr20-13785077-G-GC
• NM_024120.5:c.11dupC

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_024120.5(NDUFAF5):​c.11dupC​(p.Ala5GlyfsTer23) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. P4P) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NDUFAF5 NM_024120.5 frameshift
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: -2.51
• Publications: 0 publications found

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

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 86 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 20-13785077-G-GC is Pathogenic according to our data. Variant chr20-13785077-G-GC is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 3239844.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024120.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NDUFAF5	NM_024120.5	MANE Select	c.11dupC	p.Ala5GlyfsTer23	frameshift	Exon 1 of 11	NP_077025.2
	NDUFAF5	NM_001039375.3		c.11dupC	p.Ala5GlyfsTer23	frameshift	Exon 1 of 10	NP_001034464.1	Q5TEU4-2
	NDUFAF5	NM_001352408.2		c.11dupC	p.Ala5GlyfsTer23	frameshift	Exon 1 of 9	NP_001339337.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NDUFAF5	ENST00000378106.10	TSL:1 MANE Select	c.11dupC	p.Ala5GlyfsTer23	frameshift	Exon 1 of 11	ENSP00000367346.5	Q5TEU4-1
	NDUFAF5	ENST00000463598.1	TSL:1	c.11dupC	p.Ala5GlyfsTer23	frameshift	Exon 1 of 10	ENSP00000420497.1	Q5TEU4-2
	NDUFAF5	ENST00000874783.1		c.11dupC	p.Ala5GlyfsTer23	frameshift	Exon 1 of 12	ENSP00000544842.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Mitochondrial complex I deficiency, nuclear type 16 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-2.5

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

Other links and lift over

hg19: chr20-13765723;