11-68032155-C-T

Position:

chr11-68032155-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_002496.4(NDUFS8):c.4C>T(p.Arg2Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00269 in 1,612,352 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0019 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0028 ( 7 hom. )

Consequence

NDUFS8
NM_002496.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6B:6

Conservation

PhyloP100: -0.312

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.014999539).

BP6

Variant 11-68032155-C-T is Benign according to our data. Variant chr11-68032155-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 214836.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=6}.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00192 (292/152366) while in subpopulation NFE AF= 0.00322 (219/68036). AF 95% confidence interval is 0.00287. There are 0 homozygotes in gnomad4. There are 135 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NDUFS8	NM_002496.4 linkuse as main transcript	c.4C>T	p.Arg2Cys	missense_variant	2/7	ENST00000313468.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NDUFS8	ENST00000313468.10 linkuse as main transcript	c.4C>T	p.Arg2Cys	missense_variant	2/7	1	NM_002496.4	P1

Frequencies

GnomAD3 genomes

AF:

0.00192

AC:

292

AN:

152248

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000723

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00157

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00122

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00322

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.00166

AC:

417

AN:

251298

Hom.:

AF XY:

0.00168

AC XY:

228

AN XY:

135822

show subpopulations

Gnomad AFR exome

AF:

0.00117

Gnomad AMR exome

AF:

0.000694

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000435

Gnomad SAS exome

AF:

0.0000980

Gnomad FIN exome

AF:

0.000647

Gnomad NFE exome

AF:

0.00301

Gnomad OTH exome

AF:

0.00114

GnomAD4 exome

AF:

0.00277

AC:

4041

AN:

1459986

Hom.:

Cov.:

AF XY:

0.00267

AC XY:

1936

AN XY:

726268

show subpopulations

Gnomad4 AFR exome

AF:

0.000658

Gnomad4 AMR exome

AF:

0.000894

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000353

Gnomad4 SAS exome

AF:

0.0000464

Gnomad4 FIN exome

AF:

0.000807

Gnomad4 NFE exome

AF:

0.00339

Gnomad4 OTH exome

AF:

0.00249

GnomAD4 genome

AF:

0.00192

AC:

292

AN:

152366

Hom.:

Cov.:

AF XY:

0.00181

AC XY:

135

AN XY:

74508

show subpopulations

Gnomad4 AFR

AF:

0.000721

Gnomad4 AMR

AF:

0.00157

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00122

Gnomad4 NFE

AF:

0.00322

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.00269

Hom.:

Bravo

AF:

0.00195

TwinsUK

AF:

0.00458

AC:

ALSPAC

AF:

0.00259

AC:

ESP6500AA

AF:

0.000909

AC:

ESP6500EA

AF:

0.00314

AC:

ExAC

AF:

0.00151

AC:

183

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.00294

EpiControl

AF:

0.00302

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6Benign:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:4

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 21, 2020	This variant is associated with the following publications: (PMID: 30094188, 20818383, 26764160) -
Likely benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The NDUFS8 p.Arg2Cys variant was identified in the literature in a case with Malignant Hyperthermia Susceptibility however this patient had variants in the HMBS and CACNA1S genes that were suspected to be the cause of the phenotype (Sambuughin_2018_PMID:30094188). The variant was identified in dbSNP (ID: rs150278938) and ClinVar (classified as uncertain significance by EGL Genetic Diagnostics, Fulgent Genetics, and GeneDx, and as likely benign by Invitae). The variant was identified in control databases in 481 of 282694 chromosomes (2 homozygous) at a frequency of 0.001701 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 394 of 129024 chromosomes (freq: 0.003054), Other in 9 of 7220 chromosomes (freq: 0.001247), African in 25 of 24970 chromosomes (freq: 0.001001), Latino in 25 of 35436 chromosomes (freq: 0.000706), European (Finnish) in 17 of 25118 chromosomes (freq: 0.000677), East Asian in 8 of 19952 chromosomes (freq: 0.000401) and South Asian in 3 of 30616 chromosomes (freq: 0.000098), but was not observed in the Ashkenazi Jewish population. The p.Arg2 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 08, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jun 27, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	NDUFS8: BS2 -

Leigh syndrome

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -

Mitochondrial complex I deficiency, nuclear type 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Mitochondrial complex 1 deficiency, nuclear type 2

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Nov 14, 2023

- -

NDUFS8-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 11, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 13, 2021

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.092

BayesDel_noAF

Uncertain

0.10

CADD

Benign

DANN

Benign

0.91

DEOGEN2

Benign

0.19

T;T;T;T

Eigen

Benign

-0.28

Eigen_PC

Benign

-0.29

FATHMM_MKL

Benign

0.21

LIST_S2

Benign

0.73

T;T;T;T

M_CAP

Uncertain

0.20

MetaRNN

Benign

0.015

T;T;T;T

MetaSVM

Uncertain

0.028

MutationAssessor

Benign

0.0

N;.;.;.

MutationTaster

Benign

0.99

D;N

PrimateAI

Benign

0.36

PROVEAN

Benign

-1.0

N;N;N;N

REVEL

Uncertain

0.55

Sift

Uncertain

0.0010

D;D;D;D

Sift4G

Benign

0.13

T;T;T;T

Polyphen

0.83

P;.;P;.

Vest4

0.38

MVP

0.96

MPC

0.67

ClinPred

0.032

GERP RS

1.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.10

gMVP

0.53

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over