12-4687052-CGC-GGT

Variant names:

• chr12-4687052-CGC-GGT
• NM_005002.5:c.1078_1080delCGCinsGGT
• NDUFA9 p.Arg360Gly

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PS1 PM1 PM5

The NM_005002.5(NDUFA9):​c.1078_1080delCGCinsGGT​(p.Arg360Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R360C) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NDUFA9 NM_005002.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.25
• Publications: 0 publications found

Genes affected

NDUFA9 (HGNC:7693): (NADH:ubiquinone oxidoreductase subunit A9) The encoded protein is a subunit of the hydrophobic protein fraction of the NADH:ubiquinone oxidoreductase (complex I), the first enzyme complex in the electron transport chain located in the inner mitochondrial membrane. A pseudogene has been identified on chromosome 12. [provided by RefSeq, May 2010]

NDUFA9 Gene-Disease associations (from GenCC):

• Leigh syndrome

  Inheritance: AR Classification: MODERATE, LIMITED Submitted by: G2P, ClinGen
• Leigh syndrome with leukodystrophy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• mitochondrial complex I deficiency, nuclear type 26

  Inheritance: AR Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ENSG00000255639 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PS1: Transcript NM_005002.5 (NDUFA9) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_005002.5
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr12-4687052-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 587683.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005002.5. 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
	NDUFA9	NM_005002.5	MANE Select	c.1078_1080delCGCinsGGT	p.Arg360Gly	missense	N/A	NP_004993.1	Q16795

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NDUFA9	ENST00000266544.10	TSL:1 MANE Select	c.1078_1080delCGCinsGGT	p.Arg360Gly	missense	N/A	ENSP00000266544.5	Q16795
	ENSG00000255639	ENST00000648836.1		c.963+1727_963+1729delCGCinsGGT		intron	N/A	ENSP00000497305.1	A0A3B3ISG8
	NDUFA9	ENST00000852780.1		c.1183_1185delCGCinsGGT	p.Arg395Gly	missense	N/A	ENSP00000522839.1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.2

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr12-4796218;