10-100529767-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_005004.4(NDUFB8):c.85G>C(p.Ala29Pro) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000000685 in 1,460,788 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. A29A) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: NDUFB8 NM_005004.4 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.95

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]

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.871

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NDUFB8	NM_005004.4	c.85G>C	p.Ala29Pro	missense_variant, splice_region_variant	1/5	ENST00000299166.9
NDUFB8	NM_001284367.2	c.85G>C	p.Ala29Pro	missense_variant, splice_region_variant	1/5
NDUFB8	NM_001284368.1	c.-9+91G>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NDUFB8	ENST00000299166.9	c.85G>C	p.Ala29Pro	missense_variant, splice_region_variant	1/5	1	NM_005004.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460788 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726734

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jun 29, 2023

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. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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 disruptive. This variant has not been reported in the literature in individuals affected with NDUFB8-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 29 of the NDUFB8 protein (p.Ala29Pro). This variant also falls at the last nucleotide of exon 1, which is part of the consensus splice site for this exon. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.48
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.30
Cadd	Pathogenic	35
Dann	Uncertain	1.0
DEOGEN2	Benign	0.22	T;.
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.85	T;.
M_CAP	Uncertain	0.23	D
MetaRNN	Pathogenic	0.87	D;D
MetaSVM	Uncertain	0.12	D
MutationAssessor	Pathogenic	3.4	M;M
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.51	T
PROVEAN	Uncertain	-3.0	D;D
REVEL	Pathogenic	0.70
Sift	Uncertain	0.020	D;D
Sift4G	Benign	0.073	T;T
Polyphen		1.0	D;.
Vest4		0.78
MutPred		0.61		Loss of MoRF binding (P = 0.0533);Loss of MoRF binding (P = 0.0533);
MVP		0.64
MPC		1.0
ClinPred		1.0	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.76
gMVP		0.79

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.94		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.24		Position offset: -38
DS_DL_spliceai		0.94		Position offset: 0

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: chr10-102289524;