NM_002496.4:c.-45A>C

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 4 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

GLTC1 (HGNC:56861):

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId 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.

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.-45A>C		5_prime_UTR	Exon 1 of 7	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.-45A>C		5_prime_UTR	Exon 1 of 7	ENSP00000315774.5	O00217
	NDUFS8	ENST00000528492.1	TSL:1	c.-111A>C		5_prime_UTR	Exon 1 of 3	ENSP00000432848.1	Q08E91
	NDUFS8	ENST00000852151.1		c.-22A>C		5_prime_UTR	Exon 1 of 7	ENSP00000522210.1

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

African (AFR) AF: 0.0275 AC: 76 AN: 2764

American (AMR) AF: 0.0197 AC: 170 AN: 8620

Ashkenazi Jewish (ASJ) AF: 0.000269 AC: 1 AN: 3712

East Asian (EAS) AF: 0.0689 AC: 295 AN: 4284

South Asian (SAS) AF: 0.00561 AC: 234 AN: 41742

European-Finnish (FIN) AF: 0.0208 AC: 177 AN: 8516

Middle Eastern (MID) AF: 0.00836 AC: 5 AN: 598

European-Non Finnish (NFE) AF: 0.00129 AC: 126 AN: 98034

Other (OTH) AF: 0.00956 AC: 81 AN: 8470

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

African (AFR) AF: 0.0304 AC: 1263 AN: 41604

American (AMR) AF: 0.0168 AC: 257 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3470

East Asian (EAS) AF: 0.0787 AC: 408 AN: 5182

South Asian (SAS) AF: 0.00683 AC: 33 AN: 4830

European-Finnish (FIN) AF: 0.0269 AC: 286 AN: 10620

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.00125 AC: 85 AN: 68026

Other (OTH) AF: 0.0147 AC: 31 AN: 2114

Alfa AF: 0.00815 Hom.: 26

Bravo AF: 0.0164

Asia WGS AF: 0.0350 AC: 120 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Leigh syndrome (1)
-	-	1	Mitochondrial complex I deficiency, nuclear type 1 (1)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	9.1
DANN	Benign	0.67
PhyloP100		0.68
PromoterAI		-0.12	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=300/0	polymorphism

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

Other links and lift over

dbSNP: rs4147776; hg19: chr11-67798156;