15-41387487-G-C

Variant names:

Variant summary

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

The NM_016013.4(NDUFAF1):c.941C>G(p.Ala314Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.169 in 1,611,006 control chromosomes in the GnomAD database, including 25,466 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.13 ( 1639 hom., cov: 31)

Exomes 𝑓: 0.17 ( 23827 hom. )

Consequence

NDUFAF1
NM_016013.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 9.05

Publications

20 publications found

Variant links:

Genes affected

NDUFAF1 (HGNC:18828): (NADH:ubiquinone oxidoreductase complex assembly factor 1) This gene encodes a complex I assembly factor protein. Complex I (NADH-ubiquinone oxidoreductase) 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. The encoded protein is required for assembly of complex I, and mutations in this gene are a cause of mitochondrial complex I deficiency. Alternatively spliced transcript variants have been observed for this gene, and a pseudogene of this gene is located on the long arm of chromosome 19. [provided by RefSeq, Dec 2011]

NDUFAF1 Gene-Disease associations (from GenCC):

mitochondrial disease
Inheritance: AR Classification: MODERATE Submitted by: ClinGen
mitochondrial complex I deficiency
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
mitochondrial complex I deficiency, nuclear type 11
Inheritance: AR Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

NDUFAF1 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 (MetaRNN=0.0019097626).

BP6

Variant 15-41387487-G-C is Benign according to our data. Variant chr15-41387487-G-C is described in ClinVar as Benign. ClinVar VariationId is 129690.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.187 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016013.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
NDUFAF1	NM_016013.4	MANE Select	c.941C>G	p.Ala314Gly	missense	Exon 5 of 5	NP_057097.2
NDUFAF1	NM_001437486.1		c.941C>G	p.Ala314Gly	missense	Exon 5 of 5	NP_001424415.1
NDUFAF1	NM_001437487.1		c.941C>G	p.Ala314Gly	missense	Exon 5 of 5	NP_001424416.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NDUFAF1	ENST00000260361.9	TSL:1 MANE Select	c.941C>G	p.Ala314Gly	missense	Exon 5 of 5	ENSP00000260361.4	Q9Y375
NDUFAF1	ENST00000853315.1		c.1025C>G	p.Ala342Gly	missense	Exon 5 of 5	ENSP00000523374.1
NDUFAF1	ENST00000560978.2	TSL:3	c.941C>G	p.Ala314Gly	missense	Exon 5 of 5	ENSP00000453944.2	Q9Y375

Frequencies

GnomAD3 genomes

AF:

0.128

AC:

19476

AN:

151900

Hom.:

1637

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0342

Gnomad AMI

AF:

0.0888

Gnomad AMR

AF:

0.115

Gnomad ASJ

AF:

0.190

Gnomad EAS

AF:

0.00115

Gnomad SAS

AF:

0.0990

Gnomad FIN

AF:

0.175

Gnomad MID

AF:

0.153

Gnomad NFE

AF:

0.189

Gnomad OTH

AF:

0.149

GnomAD2 exomes

AF:

0.137

AC:

34452

AN:

251390

AF XY:

0.142

show subpopulations

Gnomad AFR exome

AF:

0.0309

Gnomad AMR exome

AF:

0.0843

Gnomad ASJ exome

AF:

0.177

Gnomad EAS exome

AF:

0.000381

Gnomad FIN exome

AF:

0.171

Gnomad NFE exome

AF:

0.187

Gnomad OTH exome

AF:

0.151

GnomAD4 exome

AF:

0.173

AC:

252328

AN:

1458988

Hom.:

23827

Cov.:

AF XY:

0.172

AC XY:

124740

AN XY:

725980

show subpopulations

African (AFR)

AF:

0.0271

AC:

908

AN:

33472

American (AMR)

AF:

0.0896

AC:

4006

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.178

AC:

4641

AN:

26104

East Asian (EAS)

AF:

0.000706

AC:

AN:

39666

South Asian (SAS)

AF:

0.112

AC:

9617

AN:

86230

European-Finnish (FIN)

AF:

0.171

AC:

9115

AN:

53406

Middle Eastern (MID)

AF:

0.160

AC:

923

AN:

5764

European-Non Finnish (NFE)

AF:

0.192

AC:

213440

AN:

1109342

Other (OTH)

AF:

0.160

AC:

9650

AN:

60286

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.452

Heterozygous variant carriers

9805

19610

29414

39219

49024

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

7220

14440

21660

28880

36100

<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:

0.128

AC:

19470

AN:

152018

Hom.:

1639

Cov.:

AF XY:

0.125

AC XY:

9288

AN XY:

74296

show subpopulations

African (AFR)

AF:

0.0341

AC:

1415

AN:

41474

American (AMR)

AF:

0.115

AC:

1757

AN:

15244

Ashkenazi Jewish (ASJ)

AF:

0.190

AC:

659

AN:

3472

East Asian (EAS)

AF:

0.00116

AC:

AN:

5188

South Asian (SAS)

AF:

0.0999

AC:

481

AN:

4816

European-Finnish (FIN)

AF:

0.175

AC:

1847

AN:

10548

Middle Eastern (MID)

AF:

0.147

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.189

AC:

12873

AN:

67964

Other (OTH)

AF:

0.146

AC:

308

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

828

1656

2484

3312

4140

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

220

440

660

880

1100

<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:

0.175

Hom.:

1940

Bravo

AF:

0.119

TwinsUK

AF:

0.195

AC:

722

ALSPAC

AF:

0.189

AC:

729

ESP6500AA

AF:

0.0370

AC:

163

ESP6500EA

AF:

0.190

AC:

1634

ExAC

AF:

0.138

AC:

16763

Asia WGS

AF:

0.0400

AC:

140

AN:

3478

EpiCase

AF:

0.192

EpiControl

AF:

0.182

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

Mitochondrial complex I deficiency, nuclear type 1 (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.57

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.25

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.31

Eigen

Pathogenic

0.77

Eigen_PC

Pathogenic

0.79

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.89

MetaRNN

Benign

0.0019

MetaSVM

Benign

-1.2

MutationAssessor

Pathogenic

3.1

PhyloP100

9.1

PrimateAI

Uncertain

0.68

PROVEAN

Uncertain

-3.7

REVEL

Uncertain

0.33

Sift

Uncertain

0.0070

Sift4G

Uncertain

0.011

Polyphen

0.95

Vest4

0.24

MPC

0.41

ClinPred

0.036

GERP RS

5.6

Varity_R

0.45

gMVP

0.59

Mutation Taster

=81/19

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over