X-119872005-G-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -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:16O:1

Conservation

PhyloP100: 3.35

Publications

28 publications found

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 Gene-Disease associations (from GenCC):

mitochondrial complex I deficiency, nuclear type 12
Inheritance: XL, AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
Leigh syndrome
Inheritance: XL Classification: MODERATE Submitted by: ClinGen
mitochondrial complex I deficiency
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

NDUFA1 links:

ENSG00000297015 (HGNC:):

ENSG00000297015 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 36974.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAd4 at 6 XL,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004541.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NDUFA1	NM_004541.4	MANE Select	c.94G>C	p.Gly32Arg	missense	Exon 1 of 3	NP_004532.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
NDUFA1	ENST00000371437.5	TSL:1 MANE Select	c.94G>C	p.Gly32Arg	missense	Exon 1 of 3	ENSP00000360492.4
NDUFA1	ENST00000927464.1		c.94G>C	p.Gly32Arg	missense	Exon 1 of 3	ENSP00000597523.1
NDUFA1	ENST00000851854.1		c.94G>C	p.Gly32Arg	missense	Exon 1 of 2	ENSP00000521913.1

Frequencies

GnomAD3 genomes

AF:

0.00617

AC:

698

AN:

113093

Hom.:

Cov.:

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

GnomAD2 exomes

AF:

0.00566

AC:

1037

AN:

183191

AF XY:

0.00542

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 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

African (AFR)

AF:

0.000645

AC:

AN:

26377

American (AMR)

AF:

0.00247

AC:

AN:

35206

Ashkenazi Jewish (ASJ)

AF:

0.00124

AC:

AN:

19377

East Asian (EAS)

AF:

0.0000331

AC:

AN:

30204

South Asian (SAS)

AF:

0.00187

AC:

101

AN:

54116

European-Finnish (FIN)

AF:

0.00802

AC:

325

AN:

40516

Middle Eastern (MID)

AF:

0.000484

AC:

AN:

4136

European-Non Finnish (NFE)

AF:

0.0103

AC:

8700

AN:

841197

Other (OTH)

AF:

0.00771

AC:

355

AN:

46063

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

338

675

1013

1350

1688

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

326

652

978

1304

1630

<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:

0.00617

AC:

698

AN:

113146

Hom.:

Cov.:

AF XY:

0.00561

AC XY:

198

AN XY:

35292

show subpopulations

African (AFR)

AF:

0.000895

AC:

AN:

31290

American (AMR)

AF:

0.00897

AC:

AN:

10817

Ashkenazi Jewish (ASJ)

AF:

0.00151

AC:

AN:

2650

East Asian (EAS)

AF:

0.00

AC:

AN:

3560

South Asian (SAS)

AF:

0.00177

AC:

AN:

2817

European-Finnish (FIN)

AF:

0.00575

AC:

AN:

6262

Middle Eastern (MID)

AF:

0.00

AC:

AN:

218

European-Non Finnish (NFE)

AF:

0.00932

AC:

497

AN:

53311

Other (OTH)

AF:

0.00520

AC:

AN:

1539

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

112

140

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:

0.00727

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

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (6)

not specified (4)

Mitochondrial complex I deficiency, nuclear type 12 (3)

Inborn genetic diseases (1)

Intellectual disability (1)

Mitochondrial complex I deficiency (2)

NDUFA1-related disorder (1)

Neurofibromatosis, type 1 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.35

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.25

CADD

Benign

(source)

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

PhyloP100

3.4

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

PromoterAI

-0.0017

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.60

gMVP

0.98

Mutation Taster

=83/17

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

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