12-4654334-C-T

Variant names:

• chr12-4654334-C-T
• NM_005002.5:c.92C>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005002.5(NDUFA9):​c.92C>T​(p.Pro31Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: NDUFA9 NM_005002.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.62

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1139988).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NDUFA9	NM_005002.5	c.92C>T	p.Pro31Leu	missense_variant	Exon 2 of 11	ENST00000266544.10	NP_004993.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NDUFA9	ENST00000266544.10	c.92C>T	p.Pro31Leu	missense_variant	Exon 2 of 11	1	NM_005002.5	ENSP00000266544.5
ENSG00000255639	ENST00000648836.1	c.92C>T	p.Pro31Leu	missense_variant	Exon 2 of 15			ENSP00000497305.1
ENSG00000272921	ENST00000536588.1	n.*92C>T		non_coding_transcript_exon_variant	Exon 3 of 7	3		ENSP00000445121.1
ENSG00000272921	ENST00000536588.1	n.*92C>T		3_prime_UTR_variant	Exon 3 of 7	3		ENSP00000445121.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Dec 11, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 31 of the NDUFA9 protein (p.Pro31Leu). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with NDUFA9-related conditions. An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The leucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.053	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	9.0
DANN	Benign	0.72
DEOGEN2	Benign	0.057	T;T;.
Eigen	Benign	-0.73
Eigen_PC	Benign	-0.71
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.74	T;T;T
M_CAP	Benign	0.0070	T
MetaRNN	Benign	0.11	T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.91	L;.;.
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.55	N;N;.
REVEL	Benign	0.15
Sift	Benign	0.20	T;D;.
Sift4G	Benign	0.10	T;T;.
Polyphen		0.0030	B;.;.
Vest4		0.27
MutPred		0.52		Loss of helix (P = 0.0104);.;Loss of helix (P = 0.0104);
MVP		0.58
MPC		0.13
ClinPred		0.11	T
GERP RS		2.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.036
gMVP		0.24

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: chr12-4763500; COSMIC: COSV104561589; COSMIC: COSV104561589;