chr19-1388539-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_024407.5(NDUFS7):c.68C>T(p.Pro23Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.592 in 1,610,648 control chromosomes in the GnomAD database, including 287,790 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.52 ( 21647 hom., cov: 33)

Exomes 𝑓: 0.60 ( 266143 hom. )

Consequence

NDUFS7
NM_024407.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.979

Publications

53 publications found

Variant links:

Genes affected

NDUFS7 (HGNC:7714): (NADH:ubiquinone oxidoreductase core subunit S7) This gene encodes a protein that is a subunit of one of the complexes that forms the mitochondrial respiratory chain. This protein is one of over 40 subunits found in complex I, the nicotinamide adenine dinucleotide (NADH):ubiquinone oxidoreductase. This complex functions in the transfer of electrons from NADH to the respiratory chain, and ubiquinone is believed to be the immediate electron acceptor for the enzyme. Mutations in this gene cause Leigh syndrome due to mitochondrial complex I deficiency, a severe neurological disorder that results in bilaterally symmetrical necrotic lesions in subcortical brain regions. [provided by RefSeq, Jul 2008]

NDUFS7 Gene-Disease associations (from GenCC):

mitochondrial complex I deficiency, nuclear type 3
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
Leigh syndrome
Inheritance: AR Classification: MODERATE 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

NDUFS7 links:

ENSG00000280486 (HGNC:):

ENSG00000280486 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=1.1169489E-5).

BP6

Variant 19-1388539-C-T is Benign according to our data. Variant chr19-1388539-C-T is described in ClinVar as Benign. ClinVar VariationId is 129702.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.619 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NDUFS7	NM_024407.5 link	c.68C>T	p.Pro23Leu	missense_variant	Exon 3 of 8	ENST00000233627.14	NP_077718.3	O75251-1Q7LD69
NDUFS7	NM_001363602.2 link	c.68C>T	p.Pro23Leu	missense_variant	Exon 3 of 8		NP_001350531.1
NDUFS7	XM_017026768.3 link	c.68C>T	p.Pro23Leu	missense_variant	Exon 3 of 4		XP_016882257.2	Q6ZS38

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NDUFS7	ENST00000233627.14 link	c.68C>T	p.Pro23Leu	missense_variant	Exon 3 of 8	1	NM_024407.5	ENSP00000233627.9		O75251-1

Frequencies

GnomAD3 genomes

AF:

0.522

AC:

79346

AN:

151926

Hom.:

21646

Cov.:

show subpopulations

Gnomad AFR

AF:

0.373

Gnomad AMI

AF:

0.771

Gnomad AMR

AF:

0.488

Gnomad ASJ

AF:

0.601

Gnomad EAS

AF:

0.322

Gnomad SAS

AF:

0.553

Gnomad FIN

AF:

0.526

Gnomad MID

AF:

0.665

Gnomad NFE

AF:

0.624

Gnomad OTH

AF:

0.570

GnomAD2 exomes

AF:

0.546

AC:

134740

AN:

246744

AF XY:

0.556

show subpopulations

Gnomad AFR exome

AF:

0.372

Gnomad AMR exome

AF:

0.499

Gnomad ASJ exome

AF:

0.606

Gnomad EAS exome

AF:

0.299

Gnomad FIN exome

AF:

0.528

Gnomad NFE exome

AF:

0.614

Gnomad OTH exome

AF:

0.566

GnomAD4 exome

AF:

0.600

AC:

874836

AN:

1458606

Hom.:

266143

Cov.:

AF XY:

0.601

AC XY:

435964

AN XY:

725652

show subpopulations

African (AFR)

AF:

0.365

AC:

12181

AN:

33410

American (AMR)

AF:

0.497

AC:

22196

AN:

44644

Ashkenazi Jewish (ASJ)

AF:

0.604

AC:

15765

AN:

26104

East Asian (EAS)

AF:

0.344

AC:

13666

AN:

39676

South Asian (SAS)

AF:

0.580

AC:

49958

AN:

86122

European-Finnish (FIN)

AF:

0.528

AC:

27641

AN:

52370

Middle Eastern (MID)

AF:

0.634

AC:

2885

AN:

4548

European-Non Finnish (NFE)

AF:

0.625

AC:

695213

AN:

1111528

Other (OTH)

AF:

0.587

AC:

35331

AN:

60204

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

19662

39324

58986

78648

98310

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

18414

36828

55242

73656

92070

<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:

0.522

AC:

79373

AN:

152042

Hom.:

21647

Cov.:

AF XY:

0.513

AC XY:

38160

AN XY:

74316

show subpopulations

African (AFR)

AF:

0.373

AC:

15455

AN:

41458

American (AMR)

AF:

0.487

AC:

7447

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.601

AC:

2084

AN:

3470

East Asian (EAS)

AF:

0.321

AC:

1657

AN:

5156

South Asian (SAS)

AF:

0.555

AC:

2680

AN:

4828

European-Finnish (FIN)

AF:

0.526

AC:

5569

AN:

10584

Middle Eastern (MID)

AF:

0.650

AC:

191

AN:

294

European-Non Finnish (NFE)

AF:

0.624

AC:

42388

AN:

67954

Other (OTH)

AF:

0.568

AC:

1200

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1897

3795

5692

7590

9487

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

700

1400

2100

2800

3500

<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:

0.584

Hom.:

86417

Bravo

AF:

0.511

TwinsUK

AF:

0.628

AC:

2328

ALSPAC

AF:

0.631

AC:

2430

ESP6500AA

AF:

0.380

AC:

1674

ESP6500EA

AF:

0.623

AC:

5353

ExAC

AF:

0.543

AC:

65719

Asia WGS

AF:

0.411

AC:

1428

AN:

3478

EpiCase

AF:

0.621

EpiControl

AF:

0.627

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Feb 19, 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

- -

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

- -

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. -

Jul 24, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Leigh syndrome

Benign:1

Jan 12, 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 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Mitochondrial complex I deficiency, nuclear type 3

Benign:1

Jul 14, 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

AlphaMissense

Benign

0.068

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.58

CADD

Benign

9.0

(source)

DANN

Benign

0.66

DEOGEN2

Benign

0.0054

.;T;T;T;.;.;.

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.21

LIST_S2

Benign

0.11

.;T;T;T;T;T;T

MetaRNN

Benign

0.000011

T;T;T;T;T;T;T

MetaSVM

Benign

-0.92

MutationAssessor

Benign

0.69

N;N;.;.;N;.;.

PhyloP100

-0.98

PrimateAI

Benign

0.43

PROVEAN

Benign

0.96

N;N;.;N;N;.;N

REVEL

Benign

0.070

Sift

Benign

0.40

T;T;.;T;T;.;T

Sift4G

Benign

0.15

T;T;T;T;T;T;T

Polyphen

0.0, 0.0010

.;B;.;B;.;.;.

Vest4

0.12

MPC

0.53

ClinPred

0.0074

GERP RS

0.84

RBP_binding_hub_radar

1.1

RBP_regulation_power_radar

2.2

Varity_R

0.023

gMVP

0.44

Mutation Taster

=97/3

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