10-100526438-C-T

Variant names:

• chr10-100526438-C-T
• rs747668007
• NM_005004.4:c.429G>A

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP3

The NM_005004.4(NDUFB8):​c.429G>A​(p.Met143Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NDUFB8 NM_005004.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.57

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]

ENSG00000255339 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM1: In a chain NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 8, mitochondrial (size 157) in uniprot entity NDUB8_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_005004.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.765

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NDUFB8	NM_005004.4	c.429G>A	p.Met143Ile	missense_variant	Exon 4 of 5	ENST00000299166.9	NP_004995.1
NDUFB8	NM_001284367.2	c.429G>A	p.Met143Ile	missense_variant	Exon 4 of 5		NP_001271296.1
NDUFB8	NM_001284368.1	c.336G>A	p.Met112Ile	missense_variant	Exon 4 of 5		NP_001271297.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NDUFB8	ENST00000299166.9	c.429G>A	p.Met143Ile	missense_variant	Exon 4 of 5	1	NM_005004.4	ENSP00000299166.4
ENSG00000255339	ENST00000557395.5	n.429G>A		non_coding_transcript_exon_variant	Exon 4 of 10	2		ENSP00000456832.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.67
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.33
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.082	T;.;.
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.74	T;T;.
M_CAP	Benign	0.017	T
MetaRNN	Pathogenic	0.77	D;D;D
MetaSVM	Benign	-0.40	T
MutationAssessor	Uncertain	2.5	M;.;M
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-1.9	N;N;N
REVEL	Uncertain	0.47
Sift	Benign	0.082	T;T;T
Sift4G	Benign	0.11	T;T;D
Polyphen		1.0	D;.;.
Vest4		0.91
MutPred		0.44		Loss of helix (P = 0.3949);.;Loss of helix (P = 0.3949);
MVP		0.63
MPC		0.50
ClinPred		0.86	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.49
gMVP		0.92

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs747668007; hg19: chr10-102286195;