10-100523925-G-C

Variant names:

• chr10-100523925-G-C
• rs536256551
• NM_005004.4:c.473C>G

Variant summary

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

The NM_005004.4(NDUFB8):​c.473C>G​(p.Pro158Arg) 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: 9.53

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, 0.795

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NDUFB8	NM_005004.4	c.473C>G	p.Pro158Arg	missense_variant	Exon 5 of 5	ENST00000299166.9	NP_004995.1
NDUFB8	NM_001284368.1	c.380C>G	p.Pro127Arg	missense_variant	Exon 5 of 5		NP_001271297.1
NDUFB8	NM_001284367.2	c.*164C>G		3_prime_UTR_variant	Exon 5 of 5		NP_001271296.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NDUFB8	ENST00000299166.9	c.473C>G	p.Pro158Arg	missense_variant	Exon 5 of 5	1	NM_005004.4	ENSP00000299166.4
ENSG00000255339	ENST00000557395.5	n.*112+52C>G		intron_variant	Intron 5 of 9	2		ENSP00000456832.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.36
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.30	T;.
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.77	T;T
M_CAP	Benign	0.016	T
MetaRNN	Pathogenic	0.80	D;D
MetaSVM	Uncertain	-0.27	T
MutationAssessor	Uncertain	2.7	M;.
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-4.4	D;D
REVEL	Uncertain	0.46
Sift	Benign	0.040	D;D
Sift4G	Uncertain	0.026	D;D
Polyphen		0.029	B;.
Vest4		0.84
MutPred		0.72		Loss of glycosylation at P158 (P = 0.0283);.;
MVP		0.64
MPC		0.37
ClinPred		0.98	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.64
gMVP		0.94

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs536256551; hg19: chr10-102283682;