X-119872005-G-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_004541.4(NDUFA1):c.94G>C(p.Gly32Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00852 in 1,210,338 control chromosomes in the GnomAD database, including 51 homozygotes. There are 3,213 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0062 ( 6 hom., 198 hem., cov: 24)

Exomes 𝑓: 0.0088 ( 45 hom. 3015 hem. )

Consequence

NDUFA1
NM_004541.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts U:2B:13O:1

Conservation

PhyloP100: 3.35

Variant links:

Genes affected

NDUFA1 (HGNC:7683): (NADH:ubiquinone oxidoreductase subunit A1) The human NDUFA1 gene codes for an essential component of complex I of the respiratory chain, which transfers electrons from NADH to ubiquinone. It has been noted that the N-terminal hydrophobic domain has the potential to be folded into an alpha-helix spanning the inner mitochondrial membrane with a C-terminal hydrophilic domain interacting with globular subunits of complex I. The highly conserved two-domain structure suggests that this feature is critical for the protein function and might act as an anchor for the NADH:ubiquinone oxidoreductase complex at the inner mitochondrial membrane. However, the NDUFA1 peptide is one of about 31 components of the "hydrophobic protein" (HP) fraction of complex I which is involved in proton translocation. Thus the NDUFA1 peptide may also participate in that function. [provided by RefSeq, Jul 2008]

NDUFA1 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.012793332).

BP6

Variant X-119872005-G-C is Benign according to our data. Variant chrX-119872005-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 36974.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-119872005-G-C is described in Lovd as [Likely_benign]. Variant chrX-119872005-G-C is described in Lovd as [Likely_pathogenic]. Variant chrX-119872005-G-C is described in Lovd as [Benign].

BS2

High Homozygotes in GnomAd at 6 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NDUFA1	NM_004541.4 linkuse as main transcript	c.94G>C	p.Gly32Arg	missense_variant	1/3	ENST00000371437.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NDUFA1	ENST00000371437.5 linkuse as main transcript	c.94G>C	p.Gly32Arg	missense_variant	1/3	1	NM_004541.4	P1

Frequencies

GnomAD3 genomes

AF:

0.00617

AC:

698

AN:

113093

Hom.:

Cov.:

AF XY:

0.00562

AC XY:

198

AN XY:

35229

show subpopulations

Gnomad AFR

AF:

0.000897

Gnomad AMI

AF:

0.0337

Gnomad AMR

AF:

0.00898

Gnomad ASJ

AF:

0.00151

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00177

Gnomad FIN

AF:

0.00575

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00932

Gnomad OTH

AF:

0.00526

GnomAD3 exomes

AF:

0.00566

AC:

1037

AN:

183191

Hom.:

AF XY:

0.00542

AC XY:

367

AN XY:

67693

show subpopulations

Gnomad AFR exome

AF:

0.000912

Gnomad AMR exome

AF:

0.00252

Gnomad ASJ exome

AF:

0.000668

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00225

Gnomad FIN exome

AF:

0.00619

Gnomad NFE exome

AF:

0.00963

Gnomad OTH exome

AF:

0.00508

GnomAD4 exome

AF:

0.00876

AC:

9612

AN:

1097192

Hom.:

Cov.:

AF XY:

0.00832

AC XY:

3015

AN XY:

362584

show subpopulations

Gnomad4 AFR exome

AF:

0.000645

Gnomad4 AMR exome

AF:

0.00247

Gnomad4 ASJ exome

AF:

0.00124

Gnomad4 EAS exome

AF:

0.0000331

Gnomad4 SAS exome

AF:

0.00187

Gnomad4 FIN exome

AF:

0.00802

Gnomad4 NFE exome

AF:

0.0103

Gnomad4 OTH exome

AF:

0.00771

GnomAD4 genome

AF:

0.00617

AC:

698

AN:

113146

Hom.:

Cov.:

AF XY:

0.00561

AC XY:

198

AN XY:

35292

show subpopulations

Gnomad4 AFR

AF:

0.000895

Gnomad4 AMR

AF:

0.00897

Gnomad4 ASJ

AF:

0.00151

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00177

Gnomad4 FIN

AF:

0.00575

Gnomad4 NFE

AF:

0.00932

Gnomad4 OTH

AF:

0.00520

Alfa

AF:

0.00727

Hom.:

153

Bravo

AF:

0.00609

TwinsUK

AF:

0.00944

AC:

ALSPAC

AF:

0.0138

AC:

ESP6500AA

AF:

0.00104

AC:

ESP6500EA

AF:

0.00996

AC:

ExAC

AF:

0.00619

AC:

752

EpiCase

AF:

0.00867

EpiControl

AF:

0.00836

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:2Benign:13Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:4

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jan 05, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 16, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 24, 2016	- -

not specified

Benign:4

Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 05, 2013	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. -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Oct 02, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 25, 2015	- -

Mitochondrial complex 1 deficiency, nuclear type 12

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 21, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jul 26, 2021	- -

Mitochondrial complex I deficiency

Uncertain:1Other:1

Uncertain significance, no assertion criteria provided	literature only	OMIM	Aug 01, 2011	- -
not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

NDUFA1-related disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 18, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 28, 2014

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.35

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.25

Cadd

Benign

Dann

Uncertain

1.0

DEOGEN2

Uncertain

0.60

FATHMM_MKL

Uncertain

0.88

LIST_S2

Benign

0.84

M_CAP

Pathogenic

0.89

MetaRNN

Benign

0.013

MetaSVM

Benign

-0.65

MutationTaster

Benign

1.0

PrimateAI

Benign

0.43

PROVEAN

Pathogenic

-6.1

REVEL

Uncertain

0.42

Sift

Benign

0.081

Sift4G

Benign

0.061

Polyphen

0.60

Vest4

0.096

MutPred

0.85

Gain of solvent accessibility (P = 0.0037);

MVP

0.69

MPC

2.1

ClinPred

0.052

GERP RS

3.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.60

gMVP

0.98

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

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