11-68036607-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_002496.4(NDUFS8):c.*14C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.172 in 1,612,862 control chromosomes in the GnomAD database, including 25,115 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.18 ( 2704 hom., cov: 33)

Exomes 𝑓: 0.17 ( 22411 hom. )

Consequence

NDUFS8
NM_002496.4 3_prime_UTR

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -0.530

Publications

18 publications found

Variant links:

Genes affected

NDUFS8 (HGNC:7715): (NADH:ubiquinone oxidoreductase core subunit S8) This gene encodes a subunit of mitochondrial NADH:ubiquinone oxidoreductase, or Complex I, a multimeric enzyme of the respiratory chain responsible for NADH oxidation, ubiquinone reduction, and the ejection of protons from mitochondria. The encoded protein is involved in the binding of two of the six to eight iron-sulfur clusters of Complex I and, as such, is required in the electron transfer process. Mutations in this gene have been associated with Leigh syndrome. [provided by RefSeq, Mar 2010]

NDUFS8 Gene-Disease associations (from GenCC):

mitochondrial complex I deficiency, nuclear type 2
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

NDUFS8 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 (BayesDel_noAF=-0.77).

BP6

Variant 11-68036607-C-T is Benign according to our data. Variant chr11-68036607-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 305774.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.237 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NDUFS8	NM_002496.4 link	c.*14C>T		3_prime_UTR_variant	Exon 7 of 7	ENST00000313468.10	NP_002487.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NDUFS8	ENST00000313468.10 link	c.*14C>T		3_prime_UTR_variant	Exon 7 of 7	1	NM_002496.4	ENSP00000315774.5

Frequencies

GnomAD3 genomes

AF:

0.182

AC:

27649

AN:

152128

Hom.:

2702

Cov.:

show subpopulations

Gnomad AFR

AF:

0.242

Gnomad AMI

AF:

0.240

Gnomad AMR

AF:

0.147

Gnomad ASJ

AF:

0.139

Gnomad EAS

AF:

0.145

Gnomad SAS

AF:

0.103

Gnomad FIN

AF:

0.0636

Gnomad MID

AF:

0.149

Gnomad NFE

AF:

0.181

Gnomad OTH

AF:

0.189

GnomAD2 exomes

AF:

0.149

AC:

37255

AN:

249630

AF XY:

0.148

show subpopulations

Gnomad AFR exome

AF:

0.242

Gnomad AMR exome

AF:

0.0998

Gnomad ASJ exome

AF:

0.150

Gnomad EAS exome

AF:

0.136

Gnomad FIN exome

AF:

0.0711

Gnomad NFE exome

AF:

0.180

Gnomad OTH exome

AF:

0.164

GnomAD4 exome

AF:

0.171

AC:

249402

AN:

1460616

Hom.:

22411

Cov.:

AF XY:

0.169

AC XY:

122963

AN XY:

726588

show subpopulations

African (AFR)

AF:

0.247

AC:

8266

AN:

33448

American (AMR)

AF:

0.106

AC:

4739

AN:

44698

Ashkenazi Jewish (ASJ)

AF:

0.152

AC:

3966

AN:

26134

East Asian (EAS)

AF:

0.161

AC:

6380

AN:

39674

South Asian (SAS)

AF:

0.102

AC:

8775

AN:

86208

European-Finnish (FIN)

AF:

0.0769

AC:

4080

AN:

53028

Middle Eastern (MID)

AF:

0.183

AC:

964

AN:

5264

European-Non Finnish (NFE)

AF:

0.182

AC:

202194

AN:

1111846

Other (OTH)

AF:

0.166

AC:

10038

AN:

60316

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

12340

24679

37019

49358

61698

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

7044

14088

21132

28176

35220

<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:

0.182

AC:

27662

AN:

152246

Hom.:

2704

Cov.:

AF XY:

0.175

AC XY:

12998

AN XY:

74448

show subpopulations

African (AFR)

AF:

0.241

AC:

10026

AN:

41534

American (AMR)

AF:

0.147

AC:

2246

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.139

AC:

483

AN:

3472

East Asian (EAS)

AF:

0.145

AC:

752

AN:

5182

South Asian (SAS)

AF:

0.103

AC:

499

AN:

4828

European-Finnish (FIN)

AF:

0.0636

AC:

676

AN:

10622

Middle Eastern (MID)

AF:

0.139

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.181

AC:

12324

AN:

67992

Other (OTH)

AF:

0.188

AC:

397

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1193

2386

3580

4773

5966

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

294

588

882

1176

1470

<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:

0.178

Hom.:

2012

Bravo

AF:

0.192

Asia WGS

AF:

0.136

AC:

471

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Leigh syndrome

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Mitochondrial complex I deficiency

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

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.

Osteopetrosis

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

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

-0.77

CADD

Benign

2.3

(source)

DANN

Benign

0.74

PhyloP100

-0.53

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

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