11-68032013-G-C

Variant names:

• chr11-68032013-G-C
• rs11824781
• NM_002496.4:c.1-139G>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_002496.4(NDUFS8):​c.1-139G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0124 in 1,250,306 control chromosomes in the GnomAD database, including 848 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.045 (479 hom., cov: 33)
  • Exomes 𝑓: 0.0078 (369 hom.)
• Consequence: NDUFS8 NM_002496.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.508
• 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 11-68032013-G-C is Benign according to our data. Variant chr11-68032013-G-C is described in ClinVar as Benign. ClinVar VariationId is 1269472.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.145 is higher than 0.05.

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.1-139G>C		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.1-139G>C		intron	N/A	ENSP00000315774.5	O00217
	NDUFS8	ENST00000528492.1	TSL:1	c.-67+1280G>C		intron	N/A	ENSP00000432848.1	Q08E91
	NDUFS8	ENST00000852154.1		c.-139G>C		5_prime_UTR_premature_start_codon_gain	Exon 1 of 6	ENSP00000522213.1

Frequencies

GnomAD3 genomes AF: 0.0453 AC: 6897 AN: 152208 Hom.: 473 Cov.: 33

Gnomad AFR AF: 0.147

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0262

Gnomad ASJ AF: 0.0118

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00497

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.00359

Gnomad OTH AF: 0.0321

GnomAD4 exome AF: 0.00785 AC: 8617 AN: 1097980 Hom.: 369 AF XY: 0.00740 AC XY: 4150 AN XY: 560636

African (AFR) AF: 0.157 AC: 4138 AN: 26286

American (AMR) AF: 0.0153 AC: 668 AN: 43614

Ashkenazi Jewish (ASJ) AF: 0.0156 AC: 370 AN: 23718

East Asian (EAS) AF: 0.0000265 AC: 1 AN: 37776

South Asian (SAS) AF: 0.00633 AC: 493 AN: 77896

European-Finnish (FIN) AF: 0.0000212 AC: 1 AN: 47164

Middle Eastern (MID) AF: 0.0364 AC: 125 AN: 3430

European-Non Finnish (NFE) AF: 0.00268 AC: 2117 AN: 789832

Other (OTH) AF: 0.0146 AC: 704 AN: 48264

GnomAD4 genome AF: 0.0455 AC: 6926 AN: 152326 Hom.: 479 Cov.: 33 AF XY: 0.0446 AC XY: 3325 AN XY: 74484

African (AFR) AF: 0.148 AC: 6136 AN: 41558

American (AMR) AF: 0.0261 AC: 400 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.0118 AC: 41 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5188

South Asian (SAS) AF: 0.00497 AC: 24 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.0442 AC: 13 AN: 294

European-Non Finnish (NFE) AF: 0.00359 AC: 244 AN: 68030

Other (OTH) AF: 0.0317 AC: 67 AN: 2112

Alfa AF: 0.0327 Hom.: 31

Bravo AF: 0.0518

Asia WGS AF: 0.00924 AC: 33 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	5.2
DANN	Benign	0.55
PhyloP100		0.51
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs11824781; hg19: chr11-67799480;