11-68034050-G-T

Variant names:

• chr11-68034050-G-T
• rs3115546
• NM_002496.4:c.372+767G>T

Variant summary

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

The NM_002496.4(NDUFS8):​c.372+767G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.932 in 154,696 control chromosomes in the GnomAD database, including 67,930 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 0.93 (66841 hom., cov: 32)
  • Exomes 𝑓: 0.94 (1089 hom.)
• Consequence: NDUFS8 NM_002496.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0770
• Publications: 5 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]

MIR4691 (HGNC:41796): (microRNA 4691) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.99 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NDUFS8	NM_002496.4	MANE Select	c.372+767G>T		intron	N/A	NP_002487.1	O00217
	MIR4691	NR_039840.1		n.*69G>T		downstream_gene	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NDUFS8	ENST00000313468.10	TSL:1 MANE Select	c.372+767G>T		intron	N/A	ENSP00000315774.5	O00217
	NDUFS8	ENST00000528492.1	TSL:1	c.-66-2203G>T		intron	N/A	ENSP00000432848.1	Q08E91
	NDUFS8	ENST00000852151.1		c.372+767G>T		intron	N/A	ENSP00000522210.1

Frequencies

GnomAD3 genomes AF: 0.932 AC: 141756 AN: 152144 Hom.: 66806 Cov.: 32

Gnomad AFR AF: 0.773

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.966

Gnomad ASJ AF: 0.986

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.995

Gnomad FIN AF: 1.00

Gnomad MID AF: 0.927

Gnomad NFE AF: 0.996

Gnomad OTH AF: 0.953

GnomAD4 exome AF: 0.943 AC: 2295 AN: 2434 Hom.: 1089 Cov.: 0 AF XY: 0.935 AC XY: 1146 AN XY: 1226

African (AFR) AF: 0.716 AC: 53 AN: 74

American (AMR) AF: 1.00 AC: 20 AN: 20

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 4 AN: 4

East Asian (EAS) AF: 1.00 AC: 2 AN: 2

South Asian (SAS) AF: 0.972 AC: 105 AN: 108

European-Finnish (FIN) AF: 1.00 AC: 6 AN: 6

Middle Eastern (MID) AF: 0.942 AC: 1539 AN: 1634

European-Non Finnish (NFE) AF: 1.00 AC: 386 AN: 386

Other (OTH) AF: 0.900 AC: 180 AN: 200

GnomAD4 genome AF: 0.932 AC: 141843 AN: 152262 Hom.: 66841 Cov.: 32 AF XY: 0.933 AC XY: 69472 AN XY: 74446

African (AFR) AF: 0.773 AC: 32062 AN: 41496

American (AMR) AF: 0.966 AC: 14779 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.986 AC: 3423 AN: 3472

East Asian (EAS) AF: 1.00 AC: 5182 AN: 5184

South Asian (SAS) AF: 0.995 AC: 4804 AN: 4828

European-Finnish (FIN) AF: 1.00 AC: 10628 AN: 10628

Middle Eastern (MID) AF: 0.925 AC: 272 AN: 294

European-Non Finnish (NFE) AF: 0.996 AC: 67766 AN: 68036

Other (OTH) AF: 0.953 AC: 2015 AN: 2114

Alfa AF: 0.971 Hom.: 87314

Bravo AF: 0.922

Asia WGS AF: 0.985 AC: 3424 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	6.7
DANN	Benign	0.44
PhyloP100		0.077
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs3115546; hg19: chr11-67801517;