2-206141952-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_005006.7(NDUFS1):c.1251A>G(p.Arg417Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.31 in 1,607,042 control chromosomes in the GnomAD database, including 79,565 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.34 ( 9320 hom., cov: 32)

Exomes 𝑓: 0.31 ( 70245 hom. )

Consequence

NDUFS1
NM_005006.7 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 0.421

Publications

17 publications found

Variant links:

Genes affected

NDUFS1 (HGNC:7707): (NADH:ubiquinone oxidoreductase core subunit S1) The protein encoded by this gene belongs to the complex I 75 kDa subunit family. Mammalian complex I is composed of 45 different subunits. It locates at the mitochondrial inner membrane. This protein has NADH dehydrogenase activity and oxidoreductase activity. It transfers electrons from NADH to the respiratory chain. The immediate electron acceptor for the enzyme is believed to be ubiquinone. This protein is the largest subunit of complex I and it is a component of the iron-sulfur (IP) fragment of the enzyme. It may form part of the active site crevice where NADH is oxidized. Mutations in this gene are associated with complex I deficiency. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2011]

NDUFS1 Gene-Disease associations (from GenCC):

Leigh syndrome
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen, G2P
mitochondrial complex I deficiency, nuclear type 5
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
mitochondrial disease
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
Leigh syndrome with leukodystrophy
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
mitochondrial complex I deficiency
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

NDUFS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.49).

BP6

Variant 2-206141952-T-C is Benign according to our data. Variant chr2-206141952-T-C is described in ClinVar as Benign. ClinVar VariationId is 129695.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.421 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.438 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NDUFS1	NM_005006.7 link	c.1251A>G	p.Arg417Arg	synonymous_variant	Exon 12 of 19	ENST00000233190.11	NP_004997.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NDUFS1	ENST00000233190.11 link	c.1251A>G	p.Arg417Arg	synonymous_variant	Exon 12 of 19	1	NM_005006.7	ENSP00000233190.5

Frequencies

GnomAD3 genomes

AF:

0.342

AC:

51977

AN:

151866

Hom.:

9315

Cov.:

show subpopulations

Gnomad AFR

AF:

0.444

Gnomad AMI

AF:

0.208

Gnomad AMR

AF:

0.294

Gnomad ASJ

AF:

0.354

Gnomad EAS

AF:

0.228

Gnomad SAS

AF:

0.240

Gnomad FIN

AF:

0.322

Gnomad MID

AF:

0.373

Gnomad NFE

AF:

0.311

Gnomad OTH

AF:

0.345

GnomAD2 exomes

AF:

0.307

AC:

77088

AN:

251248

AF XY:

0.302

show subpopulations

Gnomad AFR exome

AF:

0.445

Gnomad AMR exome

AF:

0.284

Gnomad ASJ exome

AF:

0.345

Gnomad EAS exome

AF:

0.230

Gnomad FIN exome

AF:

0.318

Gnomad NFE exome

AF:

0.317

Gnomad OTH exome

AF:

0.322

GnomAD4 exome

AF:

0.307

AC:

446709

AN:

1455058

Hom.:

70245

Cov.:

AF XY:

0.305

AC XY:

221147

AN XY:

724276

show subpopulations

African (AFR)

AF:

0.456

AC:

15165

AN:

33264

American (AMR)

AF:

0.288

AC:

12844

AN:

44664

Ashkenazi Jewish (ASJ)

AF:

0.347

AC:

9062

AN:

26084

East Asian (EAS)

AF:

0.214

AC:

8464

AN:

39626

South Asian (SAS)

AF:

0.247

AC:

21251

AN:

86020

European-Finnish (FIN)

AF:

0.320

AC:

17064

AN:

53372

Middle Eastern (MID)

AF:

0.387

AC:

2226

AN:

5758

European-Non Finnish (NFE)

AF:

0.309

AC:

341622

AN:

1106120

Other (OTH)

AF:

0.316

AC:

19011

AN:

60150

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

Heterozygous variant carriers

14370

28740

43111

57481

71851

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

11078

22156

33234

44312

55390

<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:

0.342

AC:

52018

AN:

151984

Hom.:

9320

Cov.:

AF XY:

0.339

AC XY:

25175

AN XY:

74262

show subpopulations

African (AFR)

AF:

0.443

AC:

18363

AN:

41450

American (AMR)

AF:

0.295

AC:

4498

AN:

15262

Ashkenazi Jewish (ASJ)

AF:

0.354

AC:

1230

AN:

3470

East Asian (EAS)

AF:

0.228

AC:

1175

AN:

5164

South Asian (SAS)

AF:

0.241

AC:

1164

AN:

4824

European-Finnish (FIN)

AF:

0.322

AC:

3393

AN:

10532

Middle Eastern (MID)

AF:

0.384

AC:

113

AN:

294

European-Non Finnish (NFE)

AF:

0.311

AC:

21170

AN:

67970

Other (OTH)

AF:

0.343

AC:

722

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1705

3410

5115

6820

8525

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

508

1016

1524

2032

2540

<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:

0.322

Hom.:

18748

Bravo

AF:

0.348

Asia WGS

AF:

0.237

AC:

824

AN:

3476

EpiCase

AF:

0.326

EpiControl

AF:

0.326

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 22, 2016

Mayo Clinic Laboratories, Mayo Clinic

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:2

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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. -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Leigh syndrome

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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 I deficiency, nuclear type 1

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Mitochondrial complex I deficiency, nuclear type 5

Benign:1

Sep 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.49

CADD

Benign

(source)

DANN

Benign

0.70

PhyloP100

0.42

Mutation Taster

=100/0

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over