12-4654971-G-T

Variant names:

• chr12-4654971-G-T
• rs4147672
• NM_005002.5:c.318+49G>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_005002.5(NDUFA9):​c.318+49G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000755 in 1,324,270 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.6e-7 (0 hom.)
• Consequence: NDUFA9 NM_005002.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.143
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).

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.318+49G>T		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.318+49G>T		intron	N/A	ENSP00000266544.5
	ENSG00000255639	ENST00000648836.1		c.318+49G>T		intron	N/A	ENSP00000497305.1
	NDUFA9	ENST00000396655.6	TSL:1	n.328+49G>T		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.55e-7 AC: 1 AN: 1324270 Hom.: 0 Cov.: 18 AF XY: 0.00000150 AC XY: 1 AN XY: 665178

African (AFR) AF: 0.00 AC: 0 AN: 30024

American (AMR) AF: 0.00 AC: 0 AN: 41358

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24518

East Asian (EAS) AF: 0.00 AC: 0 AN: 38970

South Asian (SAS) AF: 0.0000123 AC: 1 AN: 81066

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52950

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5428

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 994192

Other (OTH) AF: 0.00 AC: 0 AN: 55764

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.2
DANN	Benign	0.58
PhyloP100		-0.14

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: rs4147672; hg19: chr12-4764137;