rs1554843251

chr10-100526435-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP5 BP4

The NM_005004.4(NDUFB8):c.432C>G(p.Cys144Trp) 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. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: NDUFB8 NM_005004.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 2.49

Genes affected

NDUFB8 (HGNC:7703): (NADH:ubiquinone oxidoreductase subunit B8) Involved in mitochondrial respiratory chain complex I assembly. Located in endoplasmic reticulum and mitochondrion. Part of mitochondrial respiratory chain complex I. Implicated in nuclear type mitochondrial complex I deficiency 32. Biomarker of Alzheimer's disease and Parkinson's disease. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 10-100526435-G-C is Pathogenic according to our data. Variant chr10-100526435-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 548132.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr10-100526435-G-C is described in Lovd as [Pathogenic]. Variant chr10-100526435-G-C is described in Lovd as [Likely_pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.25820786).. Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NDUFB8	NM_005004.4	c.432C>G	p.Cys144Trp	missense_variant	4/5	ENST00000299166.9
NDUFB8	NM_001284367.2	c.432C>G	p.Cys144Trp	missense_variant	4/5
NDUFB8	NM_001284368.1	c.339C>G	p.Cys113Trp	missense_variant	4/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NDUFB8	ENST00000299166.9	c.432C>G	p.Cys144Trp	missense_variant	4/5	1	NM_005004.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Mitochondrial complex 1 deficiency, nuclear type 32 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 13, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.040	T
BayesDel_noAF	Benign	-0.30
Cadd	Benign	21
Dann	Uncertain	0.97
DEOGEN2	Benign	0.039	T;.;.
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.21
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.81	T;T;.
M_CAP	Benign	0.0065	T
MetaRNN	Benign	0.26	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.34	N;.;N
MutationTaster	Benign	0.98	D;D;D;D;D
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	1.8	N;N;N
REVEL	Benign	0.16
Sift	Benign	0.11	T;T;D
Sift4G	Benign	0.11	T;T;T
Polyphen		0.28	B;.;.
Vest4		0.29
MutPred		0.56		Loss of stability (P = 0.0912);.;Loss of stability (P = 0.0912);
MVP		0.57
MPC		0.47
ClinPred		0.80	D
GERP RS		3.8
Varity_R		0.62
gMVP		0.94

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs1554843251; hg19: chr10-102286192;