11-68032117-C-T

Variant names:

• chr11-68032117-C-T
• rs117961226
• NM_002496.4:c.1-35C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_002496.4(NDUFS8):​c.1-35C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0204 in 1,611,674 control chromosomes in the GnomAD database, including 432 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.017 (33 hom., cov: 33)
  • Exomes 𝑓: 0.021 (399 hom.)
• Consequence: NDUFS8 NM_002496.4 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.65
• Publications: 1 publications found

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)
• mitochondrial disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• 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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 11-68032117-C-T is Benign according to our data. Variant chr11-68032117-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1212911.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0167 (2538/152330) while in subpopulation NFE AF = 0.0249 (1694/68016). AF 95% confidence interval is 0.0239. There are 33 homozygotes in GnomAd4. There are 1204 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 33 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002496.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NDUFS8	NM_002496.4	MANE Select	c.1-35C>T		intron	N/A	NP_002487.1	O00217

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NDUFS8	ENST00000313468.10	TSL:1 MANE Select	c.1-35C>T		intron	N/A	ENSP00000315774.5	O00217
	NDUFS8	ENST00000528492.1	TSL:1	c.-67+1384C>T		intron	N/A	ENSP00000432848.1	Q08E91
	NDUFS8	ENST00000852153.1		c.-35C>T		5_prime_UTR	Exon 2 of 7	ENSP00000522212.1

Frequencies

GnomAD3 genomes AF: 0.0167 AC: 2539 AN: 152212 Hom.: 34 Cov.: 33

Gnomad AFR AF: 0.00379

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0114

Gnomad ASJ AF: 0.0216

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00331

Gnomad FIN AF: 0.0367

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0249

Gnomad OTH AF: 0.0144

GnomAD2 exomes AF: 0.0166 AC: 4168 AN: 251084 AF XY: 0.0169

Gnomad AFR exome AF: 0.00400

Gnomad AMR exome AF: 0.00607

Gnomad ASJ exome AF: 0.0216

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0319

Gnomad NFE exome AF: 0.0243

Gnomad OTH exome AF: 0.0171

GnomAD4 exome AF: 0.0208 AC: 30313 AN: 1459344 Hom.: 399 Cov.: 31 AF XY: 0.0204 AC XY: 14817 AN XY: 725976

African (AFR) AF: 0.00365 AC: 122 AN: 33412

American (AMR) AF: 0.00655 AC: 293 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.0214 AC: 559 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00425 AC: 366 AN: 86152

European-Finnish (FIN) AF: 0.0330 AC: 1753 AN: 53168

Middle Eastern (MID) AF: 0.00601 AC: 25 AN: 4162

European-Non Finnish (NFE) AF: 0.0234 AC: 25996 AN: 1111724

Other (OTH) AF: 0.0199 AC: 1199 AN: 60178

GnomAD4 genome AF: 0.0167 AC: 2538 AN: 152330 Hom.: 33 Cov.: 33 AF XY: 0.0162 AC XY: 1204 AN XY: 74490

African (AFR) AF: 0.00378 AC: 157 AN: 41584

American (AMR) AF: 0.0114 AC: 174 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.0216 AC: 75 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00352 AC: 17 AN: 4826

European-Finnish (FIN) AF: 0.0367 AC: 390 AN: 10622

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0249 AC: 1694 AN: 68016

Other (OTH) AF: 0.0142 AC: 30 AN: 2112

Alfa AF: 0.0144 Hom.: 4

Bravo AF: 0.0147

Asia WGS AF: 0.00346 AC: 12 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	5.3
DANN	Benign	0.49
PhyloP100		1.6
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs117961226; hg19: chr11-67799584;