12-4659027-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005002.5(NDUFA9):c.411-9A>T variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.258 in 1,606,668 control chromosomes in the GnomAD database, including 55,286 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.26 (5230 hom., cov: 33)
  • Exomes 𝑓: 0.26 (50056 hom.)
• Consequence: NDUFA9 NM_005002.5 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00001367
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.11

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 (BayesDel_noAF=-0.92).
• BP6: Variant 12-4659027-A-T is Benign according to our data. Variant chr12-4659027-A-T is described in ClinVar as [Benign]. Clinvar id is 138447.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-4659027-A-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.278 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NDUFA9	NM_005002.5	c.411-9A>T		splice_polypyrimidine_tract_variant, intron_variant		ENST00000266544.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NDUFA9	ENST00000266544.10	c.411-9A>T		splice_polypyrimidine_tract_variant, intron_variant		1	NM_005002.5	P1

Frequencies

GnomAD3 genomes AF: 0.259 AC: 39322 AN: 151980 Hom.: 5236 Cov.: 33

Gnomad AFR AF: 0.250

Gnomad AMI AF: 0.289

Gnomad AMR AF: 0.241

Gnomad ASJ AF: 0.364

Gnomad EAS AF: 0.192

Gnomad SAS AF: 0.172

Gnomad FIN AF: 0.199

Gnomad MID AF: 0.389

Gnomad NFE AF: 0.281

Gnomad OTH AF: 0.289

GnomAD3 exomes AF: 0.244 AC: 60822 AN: 249372 Hom.: 7783 AF XY: 0.244 AC XY: 32903 AN XY: 135038

Gnomad AFR exome AF: 0.249

Gnomad AMR exome AF: 0.209

Gnomad ASJ exome AF: 0.365

Gnomad EAS exome AF: 0.189

Gnomad SAS exome AF: 0.167

Gnomad FIN exome AF: 0.197

Gnomad NFE exome AF: 0.280

Gnomad OTH exome AF: 0.265

GnomAD4 exome AF: 0.258 AC: 375233 AN: 1454570 Hom.: 50056 Cov.: 31 AF XY: 0.257 AC XY: 186110 AN XY: 723828

Gnomad4 AFR exome AF: 0.247

Gnomad4 AMR exome AF: 0.211

Gnomad4 ASJ exome AF: 0.365

Gnomad4 EAS exome AF: 0.157

Gnomad4 SAS exome AF: 0.169

Gnomad4 FIN exome AF: 0.200

Gnomad4 NFE exome AF: 0.270

Gnomad4 OTH exome AF: 0.261

GnomAD4 genome AF: 0.259 AC: 39321 AN: 152098 Hom.: 5230 Cov.: 33 AF XY: 0.252 AC XY: 18711 AN XY: 74350

Gnomad4 AFR AF: 0.250

Gnomad4 AMR AF: 0.241

Gnomad4 ASJ AF: 0.364

Gnomad4 EAS AF: 0.191

Gnomad4 SAS AF: 0.173

Gnomad4 FIN AF: 0.199

Gnomad4 NFE AF: 0.281

Gnomad4 OTH AF: 0.287

Alfa AF: 0.279 Hom.: 2045

Bravo AF: 0.260

Asia WGS AF: 0.210 AC: 735 AN: 3478

EpiCase AF: 0.293

EpiControl AF: 0.300

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 22, 2016	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Oct 25, 2013

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
BayesDel_noAF	Benign	-0.92
Cadd	Benign	7.8
Dann	Benign	0.64

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000014
dbscSNV1_RF	Benign	0.0040
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: rs4147682; hg19: chr12-4768193;