11-68036607-C-T

Variant names:

• chr11-68036607-C-T
• rs1051806
• NM_002496.4:c.*14C>T

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.*14C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.172 in 1,612,862 control chromosomes in the GnomAD database, including 25,115 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.18 (2704 hom., cov: 33)
  • Exomes 𝑓: 0.17 (22411 hom.)
• Consequence: NDUFS8 NM_002496.4 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.530

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=-0.77).
• BP6: Variant 11-68036607-C-T is Benign according to our data. Variant chr11-68036607-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 305774.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.237 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NDUFS8	NM_002496.4	c.*14C>T		3_prime_UTR_variant	Exon 7 of 7	ENST00000313468.10	NP_002487.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NDUFS8	ENST00000313468.10	c.*14C>T		3_prime_UTR_variant	Exon 7 of 7	1	NM_002496.4	ENSP00000315774.5

Frequencies

GnomAD3 genomes AF: 0.182 AC: 27649 AN: 152128 Hom.: 2702 Cov.: 33

Gnomad AFR AF: 0.242

Gnomad AMI AF: 0.240

Gnomad AMR AF: 0.147

Gnomad ASJ AF: 0.139

Gnomad EAS AF: 0.145

Gnomad SAS AF: 0.103

Gnomad FIN AF: 0.0636

Gnomad MID AF: 0.149

Gnomad NFE AF: 0.181

Gnomad OTH AF: 0.189

GnomAD3 exomes AF: 0.149 AC: 37255 AN: 249630 Hom.: 3116 AF XY: 0.148 AC XY: 20000 AN XY: 135328

Gnomad AFR exome AF: 0.242

Gnomad AMR exome AF: 0.0998

Gnomad ASJ exome AF: 0.150

Gnomad EAS exome AF: 0.136

Gnomad SAS exome AF: 0.103

Gnomad FIN exome AF: 0.0711

Gnomad NFE exome AF: 0.180

Gnomad OTH exome AF: 0.164

GnomAD4 exome AF: 0.171 AC: 249402 AN: 1460616 Hom.: 22411 Cov.: 33 AF XY: 0.169 AC XY: 122963 AN XY: 726588

Gnomad4 AFR exome AF: 0.247

Gnomad4 AMR exome AF: 0.106

Gnomad4 ASJ exome AF: 0.152

Gnomad4 EAS exome AF: 0.161

Gnomad4 SAS exome AF: 0.102

Gnomad4 FIN exome AF: 0.0769

Gnomad4 NFE exome AF: 0.182

Gnomad4 OTH exome AF: 0.166

GnomAD4 genome AF: 0.182 AC: 27662 AN: 152246 Hom.: 2704 Cov.: 33 AF XY: 0.175 AC XY: 12998 AN XY: 74448

Gnomad4 AFR AF: 0.241

Gnomad4 AMR AF: 0.147

Gnomad4 ASJ AF: 0.139

Gnomad4 EAS AF: 0.145

Gnomad4 SAS AF: 0.103

Gnomad4 FIN AF: 0.0636

Gnomad4 NFE AF: 0.181

Gnomad4 OTH AF: 0.188

Alfa AF: 0.174 Hom.: 988

Bravo AF: 0.192

Asia WGS AF: 0.136 AC: 471 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Leigh syndrome Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mitochondrial complex I deficiency Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mitochondrial complex I deficiency, nuclear type 1 Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Osteopetrosis Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	2.3
DANN	Benign	0.74
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs1051806; hg19: chr11-67804074; COSMIC: COSV55834957; COSMIC: COSV55834957;