rs3204853

Positions:

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_StrongBA1

The NM_016013.4(NDUFAF1):c.92G>T(p.Arg31Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.233 in 1,611,294 control chromosomes in the GnomAD database, including 47,545 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.19 ( 3397 hom., cov: 31)

Exomes 𝑓: 0.24 ( 44148 hom. )

Consequence

NDUFAF1
NM_016013.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -0.815

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 links:

NDUFAF1 (HGNC:):

NDUFAF1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP6

Variant 15-41396968-C-A is Benign according to our data. Variant chr15-41396968-C-A is described in ClinVar as [Benign]. Clinvar id is 129689.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-41396968-C-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.256 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NDUFAF1	NM_016013.4 linkuse as main transcript	c.92G>T	p.Arg31Leu	missense_variant	2/5	ENST00000260361.9	NP_057097.2	Q9Y375A0A024R9L0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NDUFAF1	ENST00000260361.9 linkuse as main transcript	c.92G>T	p.Arg31Leu	missense_variant	2/5	1	NM_016013.4	ENSP00000260361.4		Q9Y375

Frequencies

GnomAD3 genomes

AF:

0.185

AC:

28163

AN:

151822

Hom.:

3399

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0489

Gnomad AMI

AF:

0.345

Gnomad AMR

AF:

0.180

Gnomad ASJ

AF:

0.258

Gnomad EAS

AF:

0.0150

Gnomad SAS

AF:

0.178

Gnomad FIN

AF:

0.303

Gnomad MID

AF:

0.161

Gnomad NFE

AF:

0.259

Gnomad OTH

AF:

0.192

GnomAD3 exomes

AF:

0.202

AC:

50286

AN:

249374

Hom.:

6127

AF XY:

0.208

AC XY:

28069

AN XY:

135090

show subpopulations

Gnomad AFR exome

AF:

0.0437

Gnomad AMR exome

AF:

0.130

Gnomad ASJ exome

AF:

0.260

Gnomad EAS exome

AF:

0.0137

Gnomad SAS exome

AF:

0.185

Gnomad FIN exome

AF:

0.301

Gnomad NFE exome

AF:

0.255

Gnomad OTH exome

AF:

0.237

GnomAD4 exome

AF:

0.238

AC:

347596

AN:

1459354

Hom.:

44148

Cov.:

AF XY:

0.238

AC XY:

172591

AN XY:

725852

show subpopulations

Gnomad4 AFR exome

AF:

0.0434

Gnomad4 AMR exome

AF:

0.135

Gnomad4 ASJ exome

AF:

0.259

Gnomad4 EAS exome

AF:

0.0153

Gnomad4 SAS exome

AF:

0.189

Gnomad4 FIN exome

AF:

0.299

Gnomad4 NFE exome

AF:

0.257

Gnomad4 OTH exome

AF:

0.223

GnomAD4 genome

AF:

0.185

AC:

28154

AN:

151940

Hom.:

3397

Cov.:

AF XY:

0.187

AC XY:

13878

AN XY:

74224

show subpopulations

Gnomad4 AFR

AF:

0.0488

Gnomad4 AMR

AF:

0.180

Gnomad4 ASJ

AF:

0.258

Gnomad4 EAS

AF:

0.0149

Gnomad4 SAS

AF:

0.177

Gnomad4 FIN

AF:

0.303

Gnomad4 NFE

AF:

0.259

Gnomad4 OTH

AF:

0.191

Alfa

AF:

0.235

Hom.:

7514

Bravo

AF:

0.171

TwinsUK

AF:

0.244

AC:

903

ALSPAC

AF:

0.257

AC:

990

ESP6500AA

AF:

0.0506

AC:

223

ESP6500EA

AF:

0.261

AC:

2242

ExAC

AF:

0.199

AC:

24191

EpiCase

AF:

0.257

EpiControl

AF:

0.257

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 19, 2016	- -

not specified

Benign:1

Likely benign, no assertion criteria provided

clinical testing

Genetic Services Laboratory, University of Chicago

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 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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. -

Mitochondrial complex 1 deficiency, nuclear type 11

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 05, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.56

CADD

Benign

4.9

DANN

Benign

0.47

DEOGEN2

Benign

0.00098

T;T;T

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.0092

LIST_S2

Benign

0.62

T;T;T

MetaRNN

Benign

0.0042

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.6

L;.;.

PrimateAI

Benign

0.19

PROVEAN

Benign

0.11

N;N;N

REVEL

Benign

0.026

Sift

Benign

0.15

T;T;T

Sift4G

Benign

0.81

T;T;T

Polyphen

0.0

B;.;.

Vest4

0.037

MPC

0.093

ClinPred

0.0027

GERP RS

-4.1

Varity_R

0.040

gMVP

0.24

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.21

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.21

Position offset: -9

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over