Genetic Variant NDUFB8:p.Tyr62His (chr10-100529408-A-G) – ACMG Classification: Uncertain_significance (5 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2PP3_ModeratePP5

The NM_005004.4(NDUFB8):c.184T>C(p.Tyr62His) 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. Variant has been reported in ClinVar as Pathogenic (no stars).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

NDUFB8
NM_005004.4 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 8.26

Publications

0 publications found

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.915

PP5

Variant 10-100529408-A-G is Pathogenic according to our data. Variant chr10-100529408-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 548134.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NDUFB8	NM_005004.4 link	c.184T>C	p.Tyr62His	missense_variant	Exon 2 of 5	ENST00000299166.9	NP_004995.1	O95169-1
NDUFB8	NM_001284367.2 link	c.184T>C	p.Tyr62His	missense_variant	Exon 2 of 5		NP_001271296.1	O95169-2
NDUFB8	NM_001284368.1 link	c.91T>C	p.Tyr31His	missense_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.184T>C	p.Tyr62His	missense_variant	Exon 2 of 5	1	NM_005004.4	ENSP00000299166.4		O95169-1
ENSG00000255339	ENST00000557395.5 link	n.184T>C		non_coding_transcript_exon_variant	Exon 2 of 10	2		ENSP00000456832.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1460274

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726428

African (AFR)

AF:

0.00

AC:

AN:

33360

American (AMR)

AF:

0.00

AC:

AN:

44276

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26060

East Asian (EAS)

AF:

0.00

AC:

AN:

39616

South Asian (SAS)

AF:

0.00

AC:

AN:

86030

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53412

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5752

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111458

Other (OTH)

AF:

0.00

AC:

AN:

60310

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Mitochondrial complex I deficiency, nuclear type 32

Pathogenic:1

Dec 13, 2018

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.96

BayesDel_addAF

Pathogenic

0.45

BayesDel_noAF

Pathogenic

0.40

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.61

D;.;.

Eigen

Pathogenic

0.84

Eigen_PC

Pathogenic

0.76

FATHMM_MKL

Uncertain

0.90

LIST_S2

Pathogenic

0.98

D;D;.

M_CAP

Uncertain

0.18

MetaRNN

Pathogenic

0.92

D;D;D

MetaSVM

Uncertain

0.33

MutationAssessor

Pathogenic

3.8

H;.;H

PhyloP100

8.3

PrimateAI

Uncertain

0.68

PROVEAN

Pathogenic

-4.7

D;D;D

REVEL

Pathogenic

0.92

Sift

Pathogenic

0.0

D;D;D

Sift4G

Uncertain

0.0070

D;D;D

Polyphen

1.0

D;.;.

Vest4

0.93

MutPred

0.72

Loss of phosphorylation at Y62 (P = 0.0098);.;Loss of phosphorylation at Y62 (P = 0.0098);

MVP

0.68

MPC

1.0

ClinPred

1.0

GERP RS

5.3

PromoterAI

-0.022

Neutral

(source)

Varity_R

0.91

gMVP

0.88

Mutation Taster

=145/155

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over