chr12-4685324-G-T

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PM5

The ENST00000266544.10(NDUFA9):​c.962G>T​(p.Arg321Leu) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000548 in 1,460,816 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R321P) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: NDUFA9 ENST00000266544.10 missense, splice_region
• Scores: Splicing: ADA: 0.09217
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.99
• Publications: 5 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: ClinGen, G2P
• 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: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr12-4685324-G-C is described in ClinVar as Pathogenic. ClinVar VariationId is 30391.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000266544.10. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NDUFA9	NM_005002.5	MANE Select	c.962G>T	p.Arg321Leu	missense splice_region	Exon 10 of 11	NP_004993.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NDUFA9	ENST00000266544.10	TSL:1 MANE Select	c.962G>T	p.Arg321Leu	missense splice_region	Exon 10 of 11	ENSP00000266544.5
	ENSG00000255639	ENST00000648836.1		c.962G>T	p.Arg321Leu	missense splice_region	Exon 10 of 15	ENSP00000497305.1
	NDUFA9	ENST00000540688.1	TSL:2	c.239G>T	p.Arg80Leu	missense splice_region	Exon 1 of 2	ENSP00000439818.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251400 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000548 AC: 8 AN: 1460816 Hom.: 0 Cov.: 31 AF XY: 0.00000826 AC XY: 6 AN XY: 726594

African (AFR) AF: 0.00 AC: 0 AN: 33452

American (AMR) AF: 0.00 AC: 0 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39658

South Asian (SAS) AF: 0.00 AC: 0 AN: 86240

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.00000720 AC: 8 AN: 1111094

Other (OTH) AF: 0.00 AC: 0 AN: 60364

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.53
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.24	T
Eigen	Uncertain	0.19
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	D
M_CAP	Uncertain	0.11	D
MetaRNN	Uncertain	0.71	D
MetaSVM	Uncertain	-0.23	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		6.0
PrimateAI	Benign	0.44	T
PROVEAN	Pathogenic	-4.7	D
REVEL	Uncertain	0.56
Sift	Benign	0.073	T
Sift4G	Benign	0.069	T
Polyphen		0.61	P
Vest4		0.76
MutPred		0.51		Loss of methylation at K318 (P = 0.0478)
MVP		0.84
MPC		0.21
ClinPred		0.99	D
GERP RS		4.2
PromoterAI		0.014	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.81
gMVP		0.93
Mutation Taster		=22/78	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.092
dbscSNV1_RF	Benign	0.36
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

dbSNP: rs199592341; hg19: chr12-4794490; COSMIC: COSV99865257; COSMIC: COSV99865257;