12-4649139-G-C

Position:

• chr12-4649139-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000266544.10(NDUFA9):​c.13G>C​(p.Ala5Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00196 in 1,604,258 control chromosomes in the GnomAD database, including 65 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A5V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.010 (30 hom., cov: 33)
  • Exomes 𝑓: 0.0011 (35 hom.)
• Consequence: NDUFA9 ENST00000266544.10 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.147

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0033494532).
• BP6: Variant 12-4649139-G-C is Benign according to our data. Variant chr12-4649139-G-C is described in ClinVar as [Benign]. Clinvar id is 138450.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-4649139-G-C is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0104 (1583/152348) while in subpopulation AFR AF= 0.036 (1498/41578). AF 95% confidence interval is 0.0345. There are 30 homozygotes in gnomad4. There are 764 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 30 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NDUFA9	NM_005002.5	c.13G>C	p.Ala5Pro	missense_variant	1/11	ENST00000266544.10	NP_004993.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NDUFA9	ENST00000266544.10	c.13G>C	p.Ala5Pro	missense_variant	1/11	1	NM_005002.5	ENSP00000266544	P1

Frequencies

GnomAD3 genomes AF: 0.0104 AC: 1578 AN: 152230 Hom.: 30 Cov.: 33

Gnomad AFR AF: 0.0360

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00445

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00669

GnomAD3 exomes AF: 0.00227 AC: 524 AN: 230680 Hom.: 12 AF XY: 0.00170 AC XY: 212 AN XY: 124478

Gnomad AFR exome AF: 0.0340

Gnomad AMR exome AF: 0.00110

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000357

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000385

Gnomad OTH exome AF: 0.000530

GnomAD4 exome AF: 0.00107 AC: 1555 AN: 1451910 Hom.: 35 Cov.: 31 AF XY: 0.000917 AC XY: 661 AN XY: 721032

Gnomad4 AFR exome AF: 0.0400

Gnomad4 AMR exome AF: 0.00129

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000595

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000199

Gnomad4 OTH exome AF: 0.00223

GnomAD4 genome AF: 0.0104 AC: 1583 AN: 152348 Hom.: 30 Cov.: 33 AF XY: 0.0103 AC XY: 764 AN XY: 74502

Gnomad4 AFR AF: 0.0360

Gnomad4 AMR AF: 0.00444

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00662

Alfa AF: 0.000491 Hom.: 0

Bravo AF: 0.0121

ESP6500AA AF: 0.0381 AC: 168

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00275 AC: 333

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Aug 04, 2017	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Feb 09, 2014

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	15
DANN	Uncertain	0.99
DEOGEN2	Benign	0.078	T;.
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.52
FATHMM_MKL	Benign	0.030	N
LIST_S2	Benign	0.64	T;T
MetaRNN	Benign	0.0033	T;T
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	1.6	L;.
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.4	N;.
REVEL	Benign	0.20
Sift	Benign	0.079	T;.
Sift4G	Benign	0.074	T;.
Polyphen		0.89	P;.
Vest4		0.34
MVP		0.67
MPC		0.33
ClinPred		0.0099	T
GERP RS		0.53
Varity_R		0.39
gMVP		0.68

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

Publications

LitVar

Other links and lift over

dbSNP: rs35155742; hg19: chr12-4758305;