12-4659027-A-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_005002.5(NDUFA9):c.411-9A>T variant causes a 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 intron

Scores

Splicing: ADA: 0.00001367

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 2.11

Publications

12 publications found

Variant links:

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)

NDUFA9 links:

ENSG00000255639 (HGNC:):

ENSG00000255639 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 138447.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 rank	MANE	Protein	UniProt
NDUFA9	NM_005002.5 link	c.411-9A>T		intron_variant	Intron 4 of 10	ENST00000266544.10	NP_004993.1	Q16795

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
NDUFA9	ENST00000266544.10 link	c.411-9A>T	intron_variant	Intron 4 of 10	1	NM_005002.5	ENSP00000266544.5	Q16795
ENSG00000255639	ENST00000648836.1 link	c.411-9A>T	intron_variant	Intron 4 of 14			ENSP00000497305.1	A0A3B3ISG8
ENSG00000272921	ENST00000536588.1 link	n.*411-9A>T	intron_variant	Intron 5 of 6	3		ENSP00000445121.1	H0YGX0

Frequencies

GnomAD3 genomes

AF:

0.259

AC:

39322

AN:

151980

Hom.:

5236

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.244

AC:

60822

AN:

249372

AF XY:

0.244

show subpopulations

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 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.:

AF XY:

0.257

AC XY:

186110

AN XY:

723828

show subpopulations

African (AFR)

AF:

0.247

AC:

8168

AN:

33094

American (AMR)

AF:

0.211

AC:

9350

AN:

44240

Ashkenazi Jewish (ASJ)

AF:

0.365

AC:

9481

AN:

26008

East Asian (EAS)

AF:

0.157

AC:

6214

AN:

39634

South Asian (SAS)

AF:

0.169

AC:

14496

AN:

85814

European-Finnish (FIN)

AF:

0.200

AC:

10686

AN:

53306

Middle Eastern (MID)

AF:

0.340

AC:

1744

AN:

5126

European-Non Finnish (NFE)

AF:

0.270

AC:

299434

AN:

1107344

Other (OTH)

AF:

0.261

AC:

15660

AN:

60004

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

11980

23960

35939

47919

59899

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

9762

19524

29286

39048

48810

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.259

AC:

39321

AN:

152098

Hom.:

5230

Cov.:

AF XY:

0.252

AC XY:

18711

AN XY:

74350

show subpopulations

African (AFR)

AF:

0.250

AC:

10370

AN:

41486

American (AMR)

AF:

0.241

AC:

3681

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.364

AC:

1265

AN:

3472

East Asian (EAS)

AF:

0.191

AC:

989

AN:

5174

South Asian (SAS)

AF:

0.173

AC:

836

AN:

4832

European-Finnish (FIN)

AF:

0.199

AC:

2100

AN:

10576

Middle Eastern (MID)

AF:

0.388

AC:

114

AN:

294

European-Non Finnish (NFE)

AF:

0.281

AC:

19095

AN:

67960

Other (OTH)

AF:

0.287

AC:

607

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1517

3034

4550

6067

7584

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

388

776

1164

1552

1940

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Feb 22, 2016

Mayo Clinic Laboratories, Mayo Clinic

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Oct 25, 2013

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

(source)

DANN

Benign

0.64

PhyloP100

2.1

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over