chr11-68032156-G-T

Position:

• chr11-68032156-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002496.4(NDUFS8):​c.5G>T​(p.Arg2Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,010 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2C) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: NDUFS8 NM_002496.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.718

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1767109).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NDUFS8	NM_002496.4	c.5G>T	p.Arg2Leu	missense_variant	2/7	ENST00000313468.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NDUFS8	ENST00000313468.10	c.5G>T	p.Arg2Leu	missense_variant	2/7	1	NM_002496.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460010 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726282

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 27, 2023

The c.5G>T (p.R2L) alteration is located in exon 2 (coding exon 1) of the NDUFS8 gene. This alteration results from a G to T substitution at nucleotide position 5, causing the arginine (R) at amino acid position 2 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Uncertain	0.026	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	12
DANN	Benign	0.92
DEOGEN2	Benign	0.18	T;T;T;T
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.75
FATHMM_MKL	Benign	0.051	N
LIST_S2	Benign	0.61	T;T;T;T
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.18	T;T;T;T
MetaSVM	Benign	-0.44	T
MutationAssessor	Benign	0.69	N;.;.;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.55	N;N;N;N
REVEL	Benign	0.26
Sift	Uncertain	0.0050	D;D;D;D
Sift4G	Benign	0.075	T;T;T;T
Polyphen		0.0060	B;.;B;.
Vest4		0.19
MutPred		0.33		Loss of MoRF binding (P = 2e-04);Loss of MoRF binding (P = 2e-04);Loss of MoRF binding (P = 2e-04);Loss of MoRF binding (P = 2e-04);
MVP		0.91
MPC		0.61
ClinPred		0.14	T
GERP RS		-1.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.062
gMVP		0.54

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs139334907; hg19: chr11-67799623;