10-100523841-A-G

Variant names:

• chr10-100523841-A-G
• rs1353153402
• NM_005004.4:c.557T>C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_005004.4(NDUFB8):​c.557T>C​(p.Ile186Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,138 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: NDUFB8 NM_005004.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.53

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 4 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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NDUFB8	NM_005004.4	c.557T>C	p.Ile186Thr	missense_variant	Exon 5 of 5	ENST00000299166.9	NP_004995.1
NDUFB8	NM_001284368.1	c.464T>C	p.Ile155Thr	missense_variant	Exon 5 of 5		NP_001271297.1
NDUFB8	NM_001284367.2	c.*248T>C		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.557T>C	p.Ile186Thr	missense_variant	Exon 5 of 5	1	NM_005004.4	ENSP00000299166.4
ENSG00000255339	ENST00000557395.5	n.*112+136T>C		intron_variant	Intron 5 of 9	2		ENSP00000456832.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152138 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152138 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74308

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.79
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.36
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.068	T;.
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.91	D;D
M_CAP	Benign	0.014	T
MetaRNN	Uncertain	0.66	D;D
MetaSVM	Uncertain	-0.12	T
MutationAssessor	Pathogenic	3.3	M;.
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-2.2	N;N
REVEL	Uncertain	0.47
Sift	Uncertain	0.0020	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.76
MutPred		0.59		Loss of stability (P = 8e-04);.;
MVP		0.50
MPC		0.97
ClinPred		0.97	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.71
gMVP		0.95

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

Publications

LitVar

Other links and lift over

dbSNP: rs1353153402; hg19: chr10-102283598;