rs150278938

chr11-68032155-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

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. 12/20 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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:6
• Conservation: PhyloP100: -0.312

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]

ACMG classification

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: {Uncertain_significance=6, Likely_benign=5}.
• 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. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NDUFS8	NM_002496.4	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	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.: 0 Cov.: 33

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.: 2 AF XY: 0.00168 AC XY: 228 AN XY: 135822

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.: 7 Cov.: 31 AF XY: 0.00267 AC XY: 1936 AN XY: 726268

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.: 0 Cov.: 33 AF XY: 0.00181 AC XY: 135 AN XY: 74508

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.: 4

Bravo AF: 0.00195

TwinsUK AF: 0.00458 AC: 17

ALSPAC AF: 0.00259 AC: 10

ESP6500AA AF: 0.000909 AC: 4

ESP6500EA AF: 0.00314 AC: 27

ExAC AF: 0.00151 AC: 183

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00294

EpiControl AF: 0.00302

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:4

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. -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 21, 2020	This variant is associated with the following publications: (PMID: 30094188, 20818383, 26764160) -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jun 27, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 08, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 22, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2023	NDUFS8: BS2 -

Leigh syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
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 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

- -

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. -

NDUFS8-related condition Benign:1

Likely benign, criteria provided, single submitter

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). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.092	T
BayesDel_noAF	Uncertain	0.10
Cadd	Benign	22
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	N
LIST_S2	Benign	0.73	T;T;T;T
M_CAP	Uncertain	0.20	D
MetaRNN	Benign	0.015	T;T;T;T
MetaSVM	Uncertain	0.028	D
MutationAssessor	Benign	0.0	N;.;.;.
MutationTaster	Benign	0.99	D;N
PrimateAI	Benign	0.36	T
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	T
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

Other links and lift over

dbSNP: rs150278938; hg19: chr11-67799622; COSMIC: COSV50288755; COSMIC: COSV50288755;