Genetic Variant NDUFAF1:p.His309Asp (chr15-41387503-G-C) – ACMG Classification: Benign (-15 pts)

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 1P and 16B. PP3BP4_StrongBP6_Very_StrongBS2

The NM_016013.4(NDUFAF1):c.925C>G(p.His309Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000883 in 1,613,566 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H309P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0017 ( 3 hom., cov: 31)

Exomes 𝑓: 0.00080 ( 11 hom. )

Consequence

NDUFAF1
NM_016013.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 9.05

Publications

5 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 -15 ACMG points.

PP3

Multiple lines of computational evidence support a deleterious effect 8: AlphaMissense, BayesDel_noAF, Eigen, MutationAssessor, phyloP100way_vertebrate, PROVEAN, REVEL, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=0.026781231).

BP6

Variant 15-41387503-G-C is Benign according to our data. Variant chr15-41387503-G-C is described in ClinVar as Benign. ClinVar VariationId is 1265556.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAd4 at 3 AR gene

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.925C>G	p.His309Asp	missense	Exon 5 of 5	NP_057097.2
NDUFAF1	NM_001437486.1		c.925C>G	p.His309Asp	missense	Exon 5 of 5	NP_001424415.1
NDUFAF1	NM_001437487.1		c.925C>G	p.His309Asp	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.925C>G	p.His309Asp	missense	Exon 5 of 5	ENSP00000260361.4	Q9Y375
NDUFAF1	ENST00000559127.5	TSL:1	n.*393C>G		non_coding_transcript_exon	Exon 6 of 6	ENSP00000453027.1	H0YL22
NDUFAF1	ENST00000559127.5	TSL:1	n.*393C>G		3_prime_UTR	Exon 6 of 6	ENSP00000453027.1	H0YL22

Frequencies

GnomAD3 genomes

AF:

0.00168

AC:

256

AN:

152126

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000966

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0194

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000632

Gnomad OTH

AF:

0.000957

GnomAD2 exomes

AF:

0.00182

AC:

457

AN:

251374

AF XY:

0.00184

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0176

Gnomad NFE exome

AF:

0.000589

Gnomad OTH exome

AF:

0.00131

GnomAD4 exome

AF:

0.000800

AC:

1169

AN:

1461322

Hom.:

Cov.:

AF XY:

0.000766

AC XY:

557

AN XY:

727030

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33474

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26128

East Asian (EAS)

AF:

0.00

AC:

AN:

39668

South Asian (SAS)

AF:

0.00

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.0160

AC:

857

AN:

53416

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.000231

AC:

257

AN:

1111510

Other (OTH)

AF:

0.000894

AC:

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

126

189

252

315

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.00168

AC:

256

AN:

152244

Hom.:

Cov.:

AF XY:

0.00247

AC XY:

184

AN XY:

74442

show subpopulations

African (AFR)

AF:

0.0000963

AC:

AN:

41550

American (AMR)

AF:

0.0000654

AC:

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.0194

AC:

206

AN:

10602

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000632

AC:

AN:

68010

Other (OTH)

AF:

0.000947

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.000332

Hom.:

Bravo

AF:

0.000170

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.00129

AC:

157

EpiCase

AF:

0.000109

EpiControl

AF:

0.000237

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.83

BayesDel_addAF

Uncertain

0.071

BayesDel_noAF

Pathogenic

0.28

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.11

Eigen

Pathogenic

0.85

Eigen_PC

Pathogenic

0.83

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.88

MetaRNN

Benign

0.027

MetaSVM

Uncertain

-0.16

MutationAssessor

Pathogenic

3.1

PhyloP100

9.1

PrimateAI

Uncertain

0.75

PROVEAN

Pathogenic

-7.9

REVEL

Pathogenic

0.67

Sift

Uncertain

0.010

Sift4G

Uncertain

0.011

Polyphen

1.0

Vest4

0.95

MVP

0.89

MPC

0.51

ClinPred

0.30

GERP RS

5.6

Varity_R

0.74

gMVP

0.84

Mutation Taster

=62/38

polymorphism

(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