chr11-68030689-A-C

Variant names:

• chr11-68030689-A-C
• rs4147776
• NM_002496.4:c.-45A>C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002496.4(NDUFS8):​c.-45A>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0107 in 329,100 control chromosomes in the GnomAD database, including 69 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.016 (49 hom., cov: 33)
  • Exomes 𝑓: 0.0066 (20 hom.)
• Consequence: NDUFS8 NM_002496.4 5_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.683

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 11-68030689-A-C is Benign according to our data. Variant chr11-68030689-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 138499.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0724 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NDUFS8	NM_002496.4	c.-45A>C		5_prime_UTR_variant	Exon 1 of 7	ENST00000313468.10	NP_002487.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NDUFS8	ENST00000313468	c.-45A>C		5_prime_UTR_variant	Exon 1 of 7	1	NM_002496.4	ENSP00000315774.5

Frequencies

GnomAD3 genomes AF: 0.0155 AC: 2359 AN: 152242 Hom.: 47 Cov.: 33

Gnomad AFR AF: 0.0303

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0164

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.0787

Gnomad SAS AF: 0.00703

Gnomad FIN AF: 0.0269

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00125

Gnomad OTH AF: 0.0153

GnomAD4 exome AF: 0.00659 AC: 1165 AN: 176740 Hom.: 20 Cov.: 0 AF XY: 0.00655 AC XY: 642 AN XY: 97958

Gnomad4 AFR exome AF: 0.0275

Gnomad4 AMR exome AF: 0.0197

Gnomad4 ASJ exome AF: 0.000269

Gnomad4 EAS exome AF: 0.0689

Gnomad4 SAS exome AF: 0.00561

Gnomad4 FIN exome AF: 0.0208

Gnomad4 NFE exome AF: 0.00129

Gnomad4 OTH exome AF: 0.00956

GnomAD4 genome AF: 0.0155 AC: 2369 AN: 152360 Hom.: 49 Cov.: 33 AF XY: 0.0172 AC XY: 1284 AN XY: 74488

Gnomad4 AFR AF: 0.0304

Gnomad4 AMR AF: 0.0168

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.0787

Gnomad4 SAS AF: 0.00683

Gnomad4 FIN AF: 0.0269

Gnomad4 NFE AF: 0.00125

Gnomad4 OTH AF: 0.0147

Alfa AF: 0.00456 Hom.: 12

Bravo AF: 0.0164

Asia WGS AF: 0.0350 AC: 120 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Dec 31, 2013

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Leigh syndrome Benign:1

Apr 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

Mitochondrial complex I deficiency, nuclear type 1 Benign:1

Apr 13, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	9.1
DANN	Benign	0.67
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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

Publications

LitVar

Other links and lift over

dbSNP: rs4147776; hg19: chr11-67798156;