rs1127566

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_005006.7(NDUFS1):c.966G>T(p.Ala322Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.441 in 1,609,870 control chromosomes in the GnomAD database, including 161,075 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A322A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.50 ( 19892 hom., cov: 33)

Exomes 𝑓: 0.43 ( 141183 hom. )

Consequence

NDUFS1
NM_005006.7 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -1.04

Publications

21 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 -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.26).

BP6

Variant 2-206144039-C-A is Benign according to our data. Variant chr2-206144039-C-A is described in ClinVar as Benign. ClinVar VariationId is 129696.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.04 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.636 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NDUFS1	NM_005006.7 link	c.966G>T	p.Ala322Ala	synonymous_variant	Exon 10 of 19	ENST00000233190.11	NP_004997.4	P28331-1E5KRK5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NDUFS1	ENST00000233190.11 link	c.966G>T	p.Ala322Ala	synonymous_variant	Exon 10 of 19	1	NM_005006.7	ENSP00000233190.5		P28331-1

Frequencies

GnomAD3 genomes

AF:

0.501

AC:

76053

AN:

151952

Hom.:

19856

Cov.:

show subpopulations

Gnomad AFR

AF:

0.642

Gnomad AMI

AF:

0.282

Gnomad AMR

AF:

0.526

Gnomad ASJ

AF:

0.546

Gnomad EAS

AF:

0.280

Gnomad SAS

AF:

0.339

Gnomad FIN

AF:

0.520

Gnomad MID

AF:

0.513

Gnomad NFE

AF:

0.434

Gnomad OTH

AF:

0.512

GnomAD2 exomes

AF:

0.454

AC:

114194

AN:

251364

AF XY:

0.445

show subpopulations

Gnomad AFR exome

AF:

0.642

Gnomad AMR exome

AF:

0.520

Gnomad ASJ exome

AF:

0.536

Gnomad EAS exome

AF:

0.287

Gnomad FIN exome

AF:

0.519

Gnomad NFE exome

AF:

0.444

Gnomad OTH exome

AF:

0.474

GnomAD4 exome

AF:

0.435

AC:

633692

AN:

1457800

Hom.:

141183

Cov.:

AF XY:

0.432

AC XY:

313373

AN XY:

725430

show subpopulations

African (AFR)

AF:

0.654

AC:

21812

AN:

33358

American (AMR)

AF:

0.522

AC:

23346

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.537

AC:

14008

AN:

26084

East Asian (EAS)

AF:

0.268

AC:

10609

AN:

39646

South Asian (SAS)

AF:

0.349

AC:

30084

AN:

86170

European-Finnish (FIN)

AF:

0.516

AC:

27524

AN:

53356

Middle Eastern (MID)

AF:

0.518

AC:

2984

AN:

5760

European-Non Finnish (NFE)

AF:

0.430

AC:

476091

AN:

1108430

Other (OTH)

AF:

0.452

AC:

27234

AN:

60284

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

Heterozygous variant carriers

16689

33378

50068

66757

83446

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

14432

28864

43296

57728

72160

<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:

0.501

AC:

76139

AN:

152070

Hom.:

19892

Cov.:

AF XY:

0.500

AC XY:

37118

AN XY:

74300

show subpopulations

African (AFR)

AF:

0.642

AC:

26631

AN:

41472

American (AMR)

AF:

0.526

AC:

8039

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.546

AC:

1893

AN:

3470

East Asian (EAS)

AF:

0.280

AC:

1446

AN:

5166

South Asian (SAS)

AF:

0.340

AC:

1639

AN:

4822

European-Finnish (FIN)

AF:

0.520

AC:

5491

AN:

10556

Middle Eastern (MID)

AF:

0.524

AC:

154

AN:

294

European-Non Finnish (NFE)

AF:

0.434

AC:

29519

AN:

67986

Other (OTH)

AF:

0.508

AC:

1071

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

1860

3719

5579

7438

9298

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

664

1328

1992

2656

3320

<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:

0.450

Hom.:

7744

Bravo

AF:

0.506

Asia WGS

AF:

0.318

AC:

1106

AN:

3478

EpiCase

AF:

0.451

EpiControl

AF:

0.462

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 03, 2015

GeneDx

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

-0.26

CADD

Benign

8.6

(source)

DANN

Benign

0.72

PhyloP100

-1.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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