rs886044765

Variant names:

• chr11-47580595-C-G
• rs886044765
• NM_004551.3:c.204C>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_004551.3(NDUFS3):​c.204C>G​(p.Ile68Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: NDUFS3 NM_004551.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.84
• Publications: 0 publications found

Genes affected

NDUFS3 (HGNC:7710): (NADH:ubiquinone oxidoreductase core subunit S3) This gene encodes one of the iron-sulfur protein (IP) components of mitochondrial NADH:ubiquinone oxidoreductase (complex I). Mutations in this gene are associated with Leigh syndrome resulting from mitochondrial complex I deficiency.[provided by RefSeq, Apr 2009]

NDUFS3 Gene-Disease associations (from GenCC):

• mitochondrial complex I deficiency, nuclear type 8

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2759636).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004551.3. 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
	NDUFS3	NM_004551.3	MANE Select	c.204C>G	p.Ile68Met	missense	Exon 3 of 7	NP_004542.1	O75489-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NDUFS3	ENST00000263774.9	TSL:1 MANE Select	c.204C>G	p.Ile68Met	missense	Exon 3 of 7	ENSP00000263774.4	O75489-1
	NDUFS3	ENST00000892082.1		c.198C>G	p.Ile66Met	missense	Exon 3 of 7	ENSP00000562141.1
	NDUFS3	ENST00000892084.1		c.204C>G	p.Ile68Met	missense	Exon 3 of 7	ENSP00000562143.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Mitochondrial complex I deficiency;C2931891:Leigh syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.019	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	19
DANN	Benign	0.97
DEOGEN2	Benign	0.19	T
Eigen	Benign	0.15
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Uncertain	0.89	D
M_CAP	Benign	0.050	D
MetaRNN	Benign	0.28	T
MetaSVM	Uncertain	-0.082	T
MutationAssessor	Benign	1.5	L
PhyloP100		1.8
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-0.54	N
REVEL	Benign	0.10
Sift	Benign	0.10	T
Sift4G	Benign	0.14	T
Polyphen		0.10	B
Vest4		0.29
MutPred		0.43		Loss of catalytic residue at P70 (P = 0.0303)
MVP		0.93
MPC		0.32
ClinPred		0.65	D
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.50
gMVP		0.41
Mutation Taster		=75/25	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: rs886044765; hg19: chr11-47602147;