12-4659453-A-G

Variant names:

• chr12-4659453-A-G
• rs7972920
• NM_005002.5:c.552+276A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_005002.5(NDUFA9):​c.552+276A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.699 in 152,082 control chromosomes in the GnomAD database, including 37,587 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.70 (37587 hom., cov: 31)
• Consequence: NDUFA9 NM_005002.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.250
• Publications: 9 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: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 12-4659453-A-G is Benign according to our data. Variant chr12-4659453-A-G is described in ClinVar as Benign. ClinVar VariationId is 682712.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.806 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NDUFA9	NM_005002.5	MANE Select	c.552+276A>G		intron	N/A	NP_004993.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NDUFA9	ENST00000266544.10	TSL:1 MANE Select	c.552+276A>G		intron	N/A	ENSP00000266544.5
	ENSG00000255639	ENST00000648836.1		c.552+276A>G		intron	N/A	ENSP00000497305.1
	NDUFA9	ENST00000396655.6	TSL:1	n.562+276A>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.699 AC: 106182 AN: 151964 Hom.: 37563 Cov.: 31

Gnomad AFR AF: 0.606

Gnomad AMI AF: 0.709

Gnomad AMR AF: 0.734

Gnomad ASJ AF: 0.632

Gnomad EAS AF: 0.807

Gnomad SAS AF: 0.828

Gnomad FIN AF: 0.801

Gnomad MID AF: 0.595

Gnomad NFE AF: 0.718

Gnomad OTH AF: 0.677

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

GnomAD4 genome AF: 0.699 AC: 106257 AN: 152082 Hom.: 37587 Cov.: 31 AF XY: 0.706 AC XY: 52510 AN XY: 74344

African (AFR) AF: 0.606 AC: 25127 AN: 41458

American (AMR) AF: 0.734 AC: 11221 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.632 AC: 2193 AN: 3472

East Asian (EAS) AF: 0.808 AC: 4186 AN: 5182

South Asian (SAS) AF: 0.827 AC: 3991 AN: 4824

European-Finnish (FIN) AF: 0.801 AC: 8475 AN: 10576

Middle Eastern (MID) AF: 0.595 AC: 175 AN: 294

European-Non Finnish (NFE) AF: 0.718 AC: 48813 AN: 67976

Other (OTH) AF: 0.679 AC: 1431 AN: 2108

Alfa AF: 0.718 Hom.: 28554

Bravo AF: 0.690

Asia WGS AF: 0.777 AC: 2697 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	5.2
DANN	Benign	0.40
PhyloP100		0.25
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs7972920; hg19: chr12-4768619;