NM_005004.4:c.210G>A

Variant names:

• chr10-100529382-C-T
• NM_005004.4:c.210G>A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The NM_005004.4(NDUFB8):​c.210G>A​(p.Met70Ile) variant causes a missense, splice region 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. 14/22 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: NDUFB8 NM_005004.4 missense, splice_region
• Scores: Splicing: ADA: 0.0009710
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.369

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:):

HIF1AN (HGNC:17113): (hypoxia inducible factor 1 subunit alpha inhibitor) Enables several functions, including 2-oxoglutarate-dependent dioxygenase activity; NF-kappaB binding activity; and transition metal ion binding activity. Involved in several processes, including negative regulation of Notch signaling pathway; negative regulation of transcription from RNA polymerase II promoter in response to hypoxia; and protein hydroxylation. Located in cytosol; nucleoplasm; and perinuclear region of cytoplasm. Colocalizes with nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 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
• BP4: Computational evidence support a benign effect (MetaRNN=0.3151633).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NDUFB8	NM_005004.4	c.210G>A	p.Met70Ile	missense_variant, splice_region_variant	Exon 2 of 5	ENST00000299166.9	NP_004995.1
NDUFB8	NM_001284367.2	c.210G>A	p.Met70Ile	missense_variant, splice_region_variant	Exon 2 of 5		NP_001271296.1
NDUFB8	NM_001284368.1	c.117G>A	p.Met39Ile	missense_variant, splice_region_variant	Exon 2 of 5		NP_001271297.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NDUFB8	ENST00000299166.9	c.210G>A	p.Met70Ile	missense_variant, splice_region_variant	Exon 2 of 5	1	NM_005004.4	ENSP00000299166.4
ENSG00000255339	ENST00000557395.5	n.210G>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 2 of 10	2		ENSP00000456832.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Jul 06, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 70 of the NDUFB8 protein (p.Met70Ile). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with NDUFB8-related conditions. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.43
BayesDel_addAF	Benign	-0.080	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	21
DANN	Uncertain	0.97
DEOGEN2	Benign	0.038	T;.;.
Eigen	Benign	-0.0061
Eigen_PC	Benign	0.077
FATHMM_MKL	Benign	0.47	N
LIST_S2	Uncertain	0.94	D;D;.
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.32	T;T;T
MetaSVM	Benign	-0.78	T
MutationAssessor	Uncertain	2.6	M;.;M
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-1.4	N;N;N
REVEL	Benign	0.085
Sift	Benign	0.20	T;T;T
Sift4G	Benign	0.22	T;T;T
Polyphen		0.30	B;.;.
Vest4		0.41
MutPred		0.35		Gain of catalytic residue at M70 (P = 0.1008);.;Gain of catalytic residue at M70 (P = 0.1008);
MVP		0.38
MPC		0.42
ClinPred		0.56	D
GERP RS		4.3
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.7
Varity_R		0.45
gMVP		0.38

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00097
dbscSNV1_RF	Benign	0.022
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

No publications associated with this variant yet.

Other links and lift over

hg19: chr10-102289139;