rs886048591

Variant names:

• chr11-68030636-G-A
• rs886048591
• ENST00000852151.1:c.-75G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The ENST00000852151.1(NDUFS8):​c.-75G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000729 in 137,246 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000073 (0 hom.)
• Consequence: NDUFS8 ENST00000852151.1 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 0.353
• Publications: 0 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: Labcorp Genetics (formerly Invitae), G2P
• 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

GLTC1 (HGNC:56861):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000852151.1. 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.-98G>A		upstream_gene	N/A	NP_002487.1	O00217
	GLTC1	NR_197583.1		n.-202C>T		upstream_gene	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NDUFS8	ENST00000852151.1		c.-75G>A		5_prime_UTR	Exon 1 of 7	ENSP00000522210.1
	NDUFS8	ENST00000432321.6	TSL:2	n.20G>A		non_coding_transcript_exon	Exon 1 of 5
	NDUFS8	ENST00000313468.10	TSL:1 MANE Select	c.-98G>A		upstream_gene	N/A	ENSP00000315774.5	O00217

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000729 AC: 1 AN: 137246 Hom.: 0 Cov.: 0 AF XY: 0.0000130 AC XY: 1 AN XY: 76954

African (AFR) AF: 0.00 AC: 0 AN: 1334

American (AMR) AF: 0.00 AC: 0 AN: 4970

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2838

East Asian (EAS) AF: 0.00 AC: 0 AN: 1866

South Asian (SAS) AF: 0.00 AC: 0 AN: 35046

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 7608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 454

European-Non Finnish (NFE) AF: 0.0000130 AC: 1 AN: 76714

Other (OTH) AF: 0.00 AC: 0 AN: 6416

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Leigh syndrome (1)
-	1	-	Mitochondrial complex I deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	7.2
DANN	Benign	0.60
PhyloP100		0.35
PromoterAI		0.056	Neutral

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs886048591; hg19: chr11-67798103;