11-68030533-G-C

Variant names:

• chr11-68030533-G-C
• rs11823975
• NM_002496.4:c.-201G>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002496.4(NDUFS8):​c.-201G>C variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0251 in 158,606 control chromosomes in the GnomAD database, including 161 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.026 (161 hom., cov: 33)
  • Exomes 𝑓: 0.00095 (0 hom.)
• Consequence: NDUFS8 NM_002496.4 upstream_gene
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.237
• Publications: 2 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

GLTC1 (HGNC:56861):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0878 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.-201G>C		upstream_gene	N/A	NP_002487.1
	GLTC1	NR_197583.1		n.-99C>G		upstream_gene	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NDUFS8	ENST00000313468.10	TSL:1 MANE Select	c.-201G>C		upstream_gene	N/A	ENSP00000315774.5
	NDUFS8	ENST00000528492.1	TSL:1	c.-267G>C		upstream_gene	N/A	ENSP00000432848.1
	NDUFS8	ENST00000526339.5	TSL:2	c.-345G>C		upstream_gene	N/A	ENSP00000436287.1

Frequencies

GnomAD3 genomes AF: 0.0261 AC: 3975 AN: 152180 Hom.: 161 Cov.: 33

Gnomad AFR AF: 0.0903

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0120

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.0163

GnomAD4 exome AF: 0.000951 AC: 6 AN: 6308 Hom.: 0 Cov.: 0 AF XY: 0.000985 AC XY: 4 AN XY: 4060

African (AFR) AF: 0.125 AC: 2 AN: 16

American (AMR) AF: 0.00578 AC: 2 AN: 346

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 44

East Asian (EAS) AF: 0.00 AC: 0 AN: 22

South Asian (SAS) AF: 0.000338 AC: 1 AN: 2958

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 306

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 10

European-Non Finnish (NFE) AF: 0.000409 AC: 1 AN: 2446

Other (OTH) AF: 0.00 AC: 0 AN: 160

GnomAD4 genome AF: 0.0261 AC: 3980 AN: 152298 Hom.: 161 Cov.: 33 AF XY: 0.0258 AC XY: 1918 AN XY: 74468

African (AFR) AF: 0.0902 AC: 3748 AN: 41554

American (AMR) AF: 0.0120 AC: 184 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

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

European-Non Finnish (NFE) AF: 0.000191 AC: 13 AN: 68022

Other (OTH) AF: 0.0161 AC: 34 AN: 2112

Alfa AF: 0.000573 Hom.: 0

Bravo AF: 0.0297

Asia WGS AF: 0.00318 AC: 12 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	6.1
DANN	Benign	0.46
PhyloP100		0.24
PromoterAI		0.014	Neutral

Splicing

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

Other links and lift over

dbSNP: rs11823975; hg19: chr11-67798000;