11-68030915-C-T

Variant names:

• chr11-68030915-C-T
• rs7949541
• NM_002496.4:c.-1+182C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_002496.4(NDUFS8):​c.-1+182C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00492 in 382,894 control chromosomes in the GnomAD database, including 22 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 0.012 (17 hom., cov: 33)
  • Exomes 𝑓: 0.0014 (5 hom.)
• Consequence: NDUFS8 NM_002496.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.661
• 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)
• 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0121 (1516/125330) while in subpopulation AFR AF = 0.0437 (1434/32826). AF 95% confidence interval is 0.0418. There are 17 homozygotes in GnomAd4. There are 724 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 17 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+182C>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+182C>T		intron	N/A	ENSP00000315774.5	O00217
	NDUFS8	ENST00000528492.1	TSL:1	c.-67+182C>T		intron	N/A	ENSP00000432848.1	Q08E91
	NDUFS8	ENST00000525419.5	TSL:3	c.9C>T	p.Arg3Arg	synonymous	Exon 1 of 4	ENSP00000433521.1	E9PKH6

Frequencies

GnomAD3 genomes AF: 0.0121 AC: 1513 AN: 125226 Hom.: 17 Cov.: 33

Gnomad AFR AF: 0.0437

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00524

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000180

Gnomad OTH AF: 0.00708

GnomAD2 exomes AF: 0.00217 AC: 231 AN: 106696 AF XY: 0.00200

Gnomad AFR exome AF: 0.0442

Gnomad AMR exome AF: 0.00174

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000127

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000919

GnomAD4 exome AF: 0.00143 AC: 368 AN: 257564 Hom.: 5 Cov.: 0 AF XY: 0.00113 AC XY: 165 AN XY: 146414

African (AFR) AF: 0.0456 AC: 289 AN: 6336

American (AMR) AF: 0.00187 AC: 44 AN: 23510

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 8238

East Asian (EAS) AF: 0.00 AC: 0 AN: 7342

South Asian (SAS) AF: 0.0000919 AC: 5 AN: 54414

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 11308

Middle Eastern (MID) AF: 0.000432 AC: 1 AN: 2316

European-Non Finnish (NFE) AF: 0.0000303 AC: 4 AN: 132200

Other (OTH) AF: 0.00210 AC: 25 AN: 11900

GnomAD4 genome AF: 0.0121 AC: 1516 AN: 125330 Hom.: 17 Cov.: 33 AF XY: 0.0117 AC XY: 724 AN XY: 61620

African (AFR) AF: 0.0437 AC: 1434 AN: 32826

American (AMR) AF: 0.00523 AC: 69 AN: 13186

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2928

East Asian (EAS) AF: 0.00 AC: 0 AN: 4286

South Asian (SAS) AF: 0.00 AC: 0 AN: 4258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9648

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 244

European-Non Finnish (NFE) AF: 0.0000180 AC: 1 AN: 55530

Other (OTH) AF: 0.00700 AC: 12 AN: 1714

Alfa AF: 0.00483 Hom.: 2

Bravo AF: 0.0118

Asia WGS AF: 0.00375 AC: 13 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	1.6
DANN	Benign	0.94
PhyloP100		-0.66
PromoterAI		0.060	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs7949541; hg19: chr11-67798382;