11-68032170-C-A

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM2 BP4_Strong BP6 BS1

The NM_002496.4(NDUFS8):c.19C>A(p.Pro7Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000187 in 1,612,734 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00074 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00013 (1 hom.)
• Consequence: NDUFS8 NM_002496.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:2
• Conservation: PhyloP100: -0.539

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 -7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.007570207).
• BP6: Variant 11-68032170-C-A is Benign according to our data. Variant chr11-68032170-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 746925.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=4, Likely_benign=2}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000742 (113/152372) while in subpopulation AFR AF= 0.00231 (96/41594). AF 95% confidence interval is 0.00193. There are 0 homozygotes in gnomad4. There are 54 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NDUFS8	NM_002496.4	c.19C>A	p.Pro7Thr	missense_variant	2/7	ENST00000313468.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NDUFS8	ENST00000313468.10	c.19C>A	p.Pro7Thr	missense_variant	2/7	1	NM_002496.4	P1

Frequencies

GnomAD3 genomes AF: 0.000729 AC: 111 AN: 152254 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00227

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000720

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.000267 AC: 67 AN: 251380 Hom.: 0 AF XY: 0.000250 AC XY: 34 AN XY: 135874

Gnomad AFR exome AF: 0.00209

Gnomad AMR exome AF: 0.000665

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.000978

GnomAD4 exome AF: 0.000129 AC: 188 AN: 1460362 Hom.: 1 Cov.: 31 AF XY: 0.000132 AC XY: 96 AN XY: 726456

Gnomad4 AFR exome AF: 0.00311

Gnomad4 AMR exome AF: 0.000626

Gnomad4 ASJ exome AF: 0.000153

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000189

Gnomad4 OTH exome AF: 0.000365

GnomAD4 genome AF: 0.000742 AC: 113 AN: 152372 Hom.: 0 Cov.: 33 AF XY: 0.000725 AC XY: 54 AN XY: 74510

Gnomad4 AFR AF: 0.00231

Gnomad4 AMR AF: 0.000719

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.000155 Hom.: 0

Bravo AF: 0.000858

ESP6500AA AF: 0.00182 AC: 8

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000288 AC: 35

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2023	NDUFS8: BP4, BS2 -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Mar 18, 2021	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Nov 27, 2023	- -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The NDUFS8 p.Pro7Thr variant was not identified in the literature nor was it identified in ClinVar, Cosmic or LOVD 3.0. The variant was identified in dbSNP (ID: rs142658611) and in control databases in 84 of 282786 chromosomes at a frequency of 0.000297 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 51 of 24972 chromosomes (freq: 0.002042), Other in 6 of 7222 chromosomes (freq: 0.000831), Latino in 23 of 35436 chromosomes (freq: 0.000649), Ashkenazi Jewish in 1 of 10364 chromosomes (freq: 0.000096), South Asian in 1 of 30616 chromosomes (freq: 0.000033) and European (non-Finnish) in 2 of 129102 chromosomes (freq: 0.000015); it was not observed in the East Asian or European (Finnish) populations. The p.Pro7 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out 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. This variant is classified as a variant of uncertain significance. -

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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled 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	Baylor Genetics	Jan 15, 2020	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.29
Cadd	Benign	6.0
Dann	Benign	0.79
DEOGEN2	Benign	0.14	T;T;T;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.058	N
LIST_S2	Benign	0.61	T;T;T;T
M_CAP	Uncertain	0.098	D
MetaRNN	Benign	0.0076	T;T;T;T
MetaSVM	Benign	-0.56	T
MutationAssessor	Benign	1.2	L;.;.;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.43	T
PROVEAN	Benign	0.060	N;N;N;N
REVEL	Benign	0.16
Sift	Benign	0.28	T;T;T;T
Sift4G	Benign	0.71	T;T;T;T
Polyphen		0.0	B;.;B;.
Vest4		0.32
MVP		0.91
MPC		0.55
ClinPred		0.00071	T
GERP RS		-2.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.025
gMVP		0.60

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs142658611; hg19: chr11-67799637;