Genetic Variant NDUFB8:p.Met140Ile (chr10-100526447-C-A) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_005004.4(NDUFB8):c.420G>T(p.Met140Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,460,094 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

NDUFB8
NM_005004.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.71

Publications

1 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 Gene-Disease associations (from GenCC):

mitochondrial complex I deficiency, nuclear type 32
Inheritance: AR, Unknown Classification: STRONG, MODERATE, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
Leigh syndrome
Inheritance: AR Classification: MODERATE Submitted by: ClinGen
Leigh syndrome with cardiomyopathy
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

NDUFB8 links:

ENSG00000255339 (HGNC:):

ENSG00000255339 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.787

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005004.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NDUFB8	NM_005004.4	MANE Select	c.420G>T	p.Met140Ile	missense	Exon 4 of 5	NP_004995.1	O95169-1
NDUFB8	NM_001284367.2		c.420G>T	p.Met140Ile	missense	Exon 4 of 5	NP_001271296.1	O95169-2
NDUFB8	NM_001284368.1		c.327G>T	p.Met109Ile	missense	Exon 4 of 5	NP_001271297.1	O95169-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NDUFB8	ENST00000299166.9	TSL:1 MANE Select	c.420G>T	p.Met140Ile	missense	Exon 4 of 5	ENSP00000299166.4	O95169-1
ENSG00000255339	ENST00000557395.5	TSL:2	n.420G>T		non_coding_transcript_exon	Exon 4 of 10	ENSP00000456832.1
NDUFB8	ENST00000937696.1		c.450G>T	p.Met150Ile	missense	Exon 4 of 5	ENSP00000607755.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1460094

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726412

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33300

American (AMR)

AF:

0.00

AC:

AN:

44160

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26054

East Asian (EAS)

AF:

0.00

AC:

AN:

39612

South Asian (SAS)

AF:

0.00

AC:

AN:

86014

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5756

European-Non Finnish (NFE)

AF:

9.00e-7

AC:

AN:

1111502

Other (OTH)

AF:

0.00

AC:

AN:

60280

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.62

BayesDel_addAF

Pathogenic

0.38

BayesDel_noAF

Pathogenic

0.30

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.084

Eigen

Uncertain

0.55

Eigen_PC

Uncertain

0.48

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.90

M_CAP

Benign

0.018

MetaRNN

Pathogenic

0.79

MetaSVM

Benign

-0.34

MutationAssessor

Pathogenic

3.0

PhyloP100

5.7

PrimateAI

Uncertain

0.61

PROVEAN

Benign

-1.5

REVEL

Uncertain

0.34

Sift

Benign

0.11

Sift4G

Benign

0.094

Polyphen

0.99

Vest4

0.85

MutPred

0.54

Loss of helix (P = 0.3949)

MVP

0.56

MPC

0.88

ClinPred

0.87

GERP RS

5.4

Varity_R

0.55

gMVP

0.91

Mutation Taster

=54/46

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over