12-4685324-G-C

Variant names:

• chr12-4685324-G-C
• rs199592341
• NM_005002.5:c.962G>C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3 PP5

The NM_005002.5(NDUFA9):​c.962G>C​(p.Arg321Pro) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000137 in 1,460,816 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: NDUFA9 NM_005002.5 missense, splice_region
• Scores: Splicing: ADA: 0.06058
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 5.99

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]

ENSG00000255639 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.814
• PP5: Variant 12-4685324-G-C is Pathogenic according to our data. Variant chr12-4685324-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 30391.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NDUFA9	NM_005002.5	c.962G>C	p.Arg321Pro	missense_variant, splice_region_variant	Exon 10 of 11	ENST00000266544.10	NP_004993.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NDUFA9	ENST00000266544.10	c.962G>C	p.Arg321Pro	missense_variant, splice_region_variant	Exon 10 of 11	1	NM_005002.5	ENSP00000266544.5
ENSG00000255639	ENST00000648836.1	c.962G>C	p.Arg321Pro	missense_variant, splice_region_variant	Exon 10 of 15			ENSP00000497305.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460816 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 726594

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Mitochondrial complex 1 deficiency, nuclear type 26 Pathogenic:1

Jan 01, 2012

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.36
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.34	T;.;.
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.92	D;D;T
M_CAP	Uncertain	0.17	D
MetaRNN	Pathogenic	0.79	D;D;D
MetaSVM	Uncertain	0.51	D
MutationAssessor	Pathogenic	3.2	M;.;.
PrimateAI	Benign	0.45	T
PROVEAN	Pathogenic	-5.1	D;D;.
REVEL	Pathogenic	0.83
Sift	Uncertain	0.0070	D;D;.
Sift4G	Uncertain	0.0070	D;D;.
Polyphen		1.0	D;.;.
Vest4		0.87
MutPred		0.53		Loss of catalytic residue at R321 (P = 0.0058);.;Loss of catalytic residue at R321 (P = 0.0058);
MVP		0.94
MPC		0.65
ClinPred		0.99	D
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.98
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.061
dbscSNV1_RF	Benign	0.33
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: rs199592341; hg19: chr12-4794490;