6-96891212-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_014165.4(NDUFAF4):c.420G>A(p.Gln140Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.881 in 1,612,936 control chromosomes in the GnomAD database, including 626,992 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.90 ( 61997 hom., cov: 31)

Exomes 𝑓: 0.88 ( 564995 hom. )

Consequence

NDUFAF4
NM_014165.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -0.0870

Publications

25 publications found

Variant links:

Genes affected

NDUFAF4 (HGNC:21034): (NADH:ubiquinone oxidoreductase complex assembly factor 4) NADH:ubiquinone oxidoreductase (complex I) catalyzes the transfer of electrons from NADH to ubiquinone (coenzyme Q) in the first step of the mitochondrial respiratory chain, resulting in the translocation of protons across the inner mitochondrial membrane. This gene encodes a complex I assembly factor. Mutations in this gene are a cause of mitochondrial complex I deficiency. [provided by RefSeq, Oct 2009]

NDUFAF4 Gene-Disease associations (from GenCC):

mitochondrial complex I deficiency, nuclear type 15
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
mitochondrial complex I deficiency
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
Leigh syndrome
Inheritance: AR Classification: LIMITED Submitted by: ClinGen

NDUFAF4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.73).

BP6

Variant 6-96891212-C-T is Benign according to our data. Variant chr6-96891212-C-T is described in ClinVar as Benign. ClinVar VariationId is 129692.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.087 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.976 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NDUFAF4	NM_014165.4 link	c.420G>A	p.Gln140Gln	synonymous_variant	Exon 3 of 3	ENST00000316149.8	NP_054884.1	Q9P032

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
NDUFAF4	ENST00000316149.8 link	c.420G>A	p.Gln140Gln	synonymous_variant	Exon 3 of 3	1	NM_014165.4	ENSP00000358272.4	Q9P032
NDUFAF4	ENST00000478382.1 link	n.355G>A		non_coding_transcript_exon_variant	Exon 2 of 2	2
NDUFAF4	ENST00000489477.1 link	n.563G>A		non_coding_transcript_exon_variant	Exon 4 of 4	3

Frequencies

GnomAD3 genomes

AF:

0.902

AC:

137051

AN:

151944

Hom.:

61936

Cov.:

show subpopulations

Gnomad AFR

AF:

0.949

Gnomad AMI

AF:

0.865

Gnomad AMR

AF:

0.919

Gnomad ASJ

AF:

0.821

Gnomad EAS

AF:

0.999

Gnomad SAS

AF:

0.909

Gnomad FIN

AF:

0.882

Gnomad MID

AF:

0.899

Gnomad NFE

AF:

0.870

Gnomad OTH

AF:

0.885

GnomAD2 exomes

AF:

0.897

AC:

224891

AN:

250838

AF XY:

0.893

show subpopulations

Gnomad AFR exome

AF:

0.953

Gnomad AMR exome

AF:

0.940

Gnomad ASJ exome

AF:

0.808

Gnomad EAS exome

AF:

0.999

Gnomad FIN exome

AF:

0.882

Gnomad NFE exome

AF:

0.868

Gnomad OTH exome

AF:

0.882

GnomAD4 exome

AF:

0.879

AC:

1284086

AN:

1460874

Hom.:

564995

Cov.:

AF XY:

0.879

AC XY:

638890

AN XY:

726780

show subpopulations

African (AFR)

AF:

0.949

AC:

31747

AN:

33456

American (AMR)

AF:

0.936

AC:

41797

AN:

44668

Ashkenazi Jewish (ASJ)

AF:

0.812

AC:

21207

AN:

26110

East Asian (EAS)

AF:

0.999

AC:

39637

AN:

39662

South Asian (SAS)

AF:

0.903

AC:

77865

AN:

86228

European-Finnish (FIN)

AF:

0.877

AC:

46800

AN:

53358

Middle Eastern (MID)

AF:

0.866

AC:

4988

AN:

5762

European-Non Finnish (NFE)

AF:

0.870

AC:

966443

AN:

1111278

Other (OTH)

AF:

0.888

AC:

53602

AN:

60352

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.457

Heterozygous variant carriers

8081

16162

24243

32324

40405

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

21314

42628

63942

85256

106570

<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:

0.902

AC:

137172

AN:

152062

Hom.:

61997

Cov.:

AF XY:

0.905

AC XY:

67276

AN XY:

74322

show subpopulations

African (AFR)

AF:

0.949

AC:

39368

AN:

41490

American (AMR)

AF:

0.919

AC:

14040

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.821

AC:

2849

AN:

3470

East Asian (EAS)

AF:

0.999

AC:

5166

AN:

5170

South Asian (SAS)

AF:

0.910

AC:

4383

AN:

4818

European-Finnish (FIN)

AF:

0.882

AC:

9306

AN:

10556

Middle Eastern (MID)

AF:

0.898

AC:

264

AN:

294

European-Non Finnish (NFE)

AF:

0.870

AC:

59138

AN:

67964

Other (OTH)

AF:

0.886

AC:

1874

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

677

1355

2032

2710

3387

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

906

1812

2718

3624

4530

<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:

0.882

Hom.:

184038

Bravo

AF:

0.907

Asia WGS

AF:

0.956

AC:

3324

AN:

3476

EpiCase

AF:

0.870

EpiControl

AF:

0.868

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Feb 19, 2016

Mayo Clinic Laboratories, Mayo Clinic

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Mitochondrial complex I deficiency, nuclear type 15

Benign:1

Sep 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mitochondrial complex I deficiency, nuclear type 1

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.73

CADD

Benign

1.6

(source)

DANN

Benign

0.42

PhyloP100

-0.087

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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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