NM_002496.4:c.*96C>T

Variant names:

• chr11-68036689-C-T
• rs3133269
• NM_002496.4:c.*96C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002496.4(NDUFS8):​c.*96C>T variant causes a downstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.74 in 1,579,622 control chromosomes in the GnomAD database, including 434,531 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.72 (40086 hom., cov: 34)
  • Exomes 𝑓: 0.74 (394445 hom.)
• Consequence: NDUFS8 NM_002496.4 downstream_gene
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0840
• Publications: 21 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)
• 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=-0.8).
• BP6: Variant 11-68036689-C-T is Benign according to our data. Variant chr11-68036689-C-T is described in ClinVar as Benign. ClinVar VariationId is 1271580.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.799 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NDUFS8	NM_002496.4	MANE Select	c.*96C>T		downstream_gene	N/A	NP_002487.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NDUFS8	ENST00000313468.10	TSL:1 MANE Select	c.*96C>T		downstream_gene	N/A	ENSP00000315774.5
	NDUFS8	ENST00000528492.1	TSL:1	c.*96C>T		downstream_gene	N/A	ENSP00000432848.1
	NDUFS8	ENST00000852151.1		c.*96C>T		downstream_gene	N/A	ENSP00000522210.1

Frequencies

GnomAD3 genomes AF: 0.725 AC: 110243 AN: 152086 Hom.: 40054 Cov.: 34

Gnomad AFR AF: 0.691

Gnomad AMI AF: 0.605

Gnomad AMR AF: 0.783

Gnomad ASJ AF: 0.778

Gnomad EAS AF: 0.820

Gnomad SAS AF: 0.769

Gnomad FIN AF: 0.621

Gnomad MID AF: 0.835

Gnomad NFE AF: 0.736

Gnomad OTH AF: 0.765

GnomAD4 exome AF: 0.742 AC: 1059371 AN: 1427418 Hom.: 394445 Cov.: 26 AF XY: 0.743 AC XY: 527021 AN XY: 709102

African (AFR) AF: 0.689 AC: 22360 AN: 32466

American (AMR) AF: 0.836 AC: 34859 AN: 41700

Ashkenazi Jewish (ASJ) AF: 0.787 AC: 20160 AN: 25604

East Asian (EAS) AF: 0.846 AC: 32255 AN: 38124

South Asian (SAS) AF: 0.773 AC: 64604 AN: 83538

European-Finnish (FIN) AF: 0.625 AC: 31210 AN: 49962

Middle Eastern (MID) AF: 0.814 AC: 3355 AN: 4124

European-Non Finnish (NFE) AF: 0.738 AC: 806998 AN: 1092952

Other (OTH) AF: 0.739 AC: 43570 AN: 58948

GnomAD4 genome AF: 0.725 AC: 110327 AN: 152204 Hom.: 40086 Cov.: 34 AF XY: 0.722 AC XY: 53764 AN XY: 74416

African (AFR) AF: 0.691 AC: 28690 AN: 41532

American (AMR) AF: 0.783 AC: 11982 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.778 AC: 2701 AN: 3472

East Asian (EAS) AF: 0.820 AC: 4229 AN: 5160

South Asian (SAS) AF: 0.767 AC: 3705 AN: 4830

European-Finnish (FIN) AF: 0.621 AC: 6590 AN: 10606

Middle Eastern (MID) AF: 0.827 AC: 243 AN: 294

European-Non Finnish (NFE) AF: 0.736 AC: 50017 AN: 67988

Other (OTH) AF: 0.766 AC: 1619 AN: 2114

Alfa AF: 0.743 Hom.: 106940

Bravo AF: 0.740

Asia WGS AF: 0.779 AC: 2710 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: 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	-0.80
CADD	Benign	2.9
DANN	Benign	0.75
PhyloP100		0.084
Mutation Taster		=98/2	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs3133269; hg19: chr11-67804156;