rs11548670

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.414T>C(p.Asp138Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0393 in 1,613,942 control chromosomes in the GnomAD database, including 1,501 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.056 ( 322 hom., cov: 32)

Exomes 𝑓: 0.038 ( 1179 hom. )

Consequence

NDUFS1
NM_005006.7 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 0.735

Publications

11 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=-0.5).

BP6

Variant 2-206147759-A-G is Benign according to our data. Variant chr2-206147759-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 138473.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.735 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0995 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NDUFS1	NM_005006.7 link	c.414T>C	p.Asp138Asp	synonymous_variant	Exon 6 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.414T>C	p.Asp138Asp	synonymous_variant	Exon 6 of 19	1	NM_005006.7	ENSP00000233190.5		P28331-1

Frequencies

GnomAD3 genomes

AF:

0.0565

AC:

8587

AN:

152110

Hom.:

322

Cov.:

show subpopulations

Gnomad AFR

AF:

0.102

Gnomad AMI

AF:

0.0220

Gnomad AMR

AF:

0.0314

Gnomad ASJ

AF:

0.0383

Gnomad EAS

AF:

0.0520

Gnomad SAS

AF:

0.0645

Gnomad FIN

AF:

0.0736

Gnomad MID

AF:

0.0348

Gnomad NFE

AF:

0.0331

Gnomad OTH

AF:

0.0469

GnomAD2 exomes

AF:

0.0481

AC:

12107

AN:

251470

AF XY:

0.0478

show subpopulations

Gnomad AFR exome

AF:

0.101

Gnomad AMR exome

AF:

0.0425

Gnomad ASJ exome

AF:

0.0424

Gnomad EAS exome

AF:

0.0561

Gnomad FIN exome

AF:

0.0746

Gnomad NFE exome

AF:

0.0333

Gnomad OTH exome

AF:

0.0396

GnomAD4 exome

AF:

0.0375

AC:

54864

AN:

1461714

Hom.:

1179

Cov.:

AF XY:

0.0382

AC XY:

27781

AN XY:

727176

show subpopulations

African (AFR)

AF:

0.105

AC:

3517

AN:

33474

American (AMR)

AF:

0.0402

AC:

1796

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0405

AC:

1059

AN:

26134

East Asian (EAS)

AF:

0.0535

AC:

2122

AN:

39696

South Asian (SAS)

AF:

0.0616

AC:

5314

AN:

86252

European-Finnish (FIN)

AF:

0.0730

AC:

3900

AN:

53420

Middle Eastern (MID)

AF:

0.0238

AC:

137

AN:

5768

European-Non Finnish (NFE)

AF:

0.0311

AC:

34529

AN:

1111856

Other (OTH)

AF:

0.0412

AC:

2490

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

3057

6114

9170

12227

15284

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0564

AC:

8590

AN:

152228

Hom.:

322

Cov.:

AF XY:

0.0568

AC XY:

4231

AN XY:

74448

show subpopulations

African (AFR)

AF:

0.102

AC:

4239

AN:

41528

American (AMR)

AF:

0.0313

AC:

478

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.0383

AC:

133

AN:

3472

East Asian (EAS)

AF:

0.0519

AC:

269

AN:

5180

South Asian (SAS)

AF:

0.0646

AC:

312

AN:

4830

European-Finnish (FIN)

AF:

0.0736

AC:

781

AN:

10608

Middle Eastern (MID)

AF:

0.0374

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0331

AC:

2250

AN:

68006

Other (OTH)

AF:

0.0460

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

388

776

1163

1551

1939

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0396

Hom.:

180

Bravo

AF:

0.0546

Asia WGS

AF:

0.0530

AC:

183

AN:

3478

EpiCase

AF:

0.0284

EpiControl

AF:

0.0307

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 23, 2016

Mayo Clinic Laboratories, Mayo Clinic

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:2

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 13, 2012

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

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:Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.50

CADD

Benign

(source)

DANN

Benign

0.60

PhyloP100

0.73

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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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rs11548670

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