Genetic Variant NDUFB8:p.Ala29Ala (chr10-100529505-G-A) – ACMG Classification: Likely_benign (-3 pts)

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBP7

The NM_005004.4(NDUFB8):c.87C>T(p.Ala29Ala) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000411 in 1,459,480 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

NDUFB8
NM_005004.4 splice_region, synonymous

Scores

Splicing: ADA: 0.00001946

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.242

Variant links:

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]

NDUFB8 links:

ENSG00000255339 (HGNC:):

ENSG00000255339 links:

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]

HIF1AN links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.64).

BP7

Synonymous conserved (PhyloP=0.242 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NDUFB8	NM_005004.4 link	c.87C>T	p.Ala29Ala	splice_region_variant, synonymous_variant	Exon 2 of 5	ENST00000299166.9	NP_004995.1	O95169-1
NDUFB8	NM_001284368.1 link	c.-7C>T		splice_region_variant	Exon 2 of 5		NP_001271297.1	O95169-3
NDUFB8	NM_001284367.2 link	c.87C>T	p.Ala29Ala	splice_region_variant, synonymous_variant	Exon 2 of 5		NP_001271296.1	O95169-2
NDUFB8	NM_001284368.1 link	c.-7C>T		5_prime_UTR_variant	Exon 2 of 5		NP_001271297.1	O95169-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NDUFB8	ENST00000299166.9 link	c.87C>T	p.Ala29Ala	splice_region_variant, synonymous_variant	Exon 2 of 5	1	NM_005004.4	ENSP00000299166.4		O95169-1
ENSG00000255339	ENST00000557395.5 link	n.87C>T		splice_region_variant, non_coding_transcript_exon_variant	Exon 2 of 10	2		ENSP00000456832.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000806

AC:

AN:

248116

Hom.:

AF XY:

0.00000744

AC XY:

AN XY:

134420

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000177

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000411

AC:

AN:

1459480

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

726206

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000450

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.64

CADD

Benign

7.6

DANN

Benign

0.80

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000019

dbscSNV1_RF

Benign

0.0

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over