rs1239013578

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2PM5PP3_Strong

The NM_005004.4(NDUFB8):c.227C>T(p.Pro76Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000041 in 1,461,786 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P76Q) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

NDUFB8
NM_005004.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 9.40

Publications

3 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, Ambry Genetics, Labcorp Genetics (formerly Invitae)
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: Likely_pathogenic. The variant received 8 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr10-100527060-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 548131.Status of the report is no_assertion_criteria_provided, 0 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.968

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NDUFB8	NM_005004.4 link	c.227C>T	p.Pro76Leu	missense_variant	Exon 3 of 5	ENST00000299166.9	NP_004995.1	O95169-1
NDUFB8	NM_001284367.2 link	c.227C>T	p.Pro76Leu	missense_variant	Exon 3 of 5		NP_001271296.1	O95169-2
NDUFB8	NM_001284368.1 link	c.134C>T	p.Pro45Leu	missense_variant	Exon 3 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.227C>T	p.Pro76Leu	missense_variant	Exon 3 of 5	1	NM_005004.4	ENSP00000299166.4		O95169-1
ENSG00000255339	ENST00000557395.5 link	n.227C>T		non_coding_transcript_exon_variant	Exon 3 of 10	2		ENSP00000456832.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251398

AF XY:

0.00000736

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000410

AC:

AN:

1461786

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

727200

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86240

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00000540

AC:

AN:

1111950

Other (OTH)

AF:

0.00

AC:

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.81

BayesDel_addAF

Pathogenic

0.51

BayesDel_noAF

Pathogenic

0.49

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.53

D;.;.

Eigen

Pathogenic

0.92

Eigen_PC

Pathogenic

0.88

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.89

D;D;.

M_CAP

Benign

0.059

MetaRNN

Pathogenic

0.97

D;D;D

MetaSVM

Uncertain

0.21

MutationAssessor

Pathogenic

3.5

M;.;M

PhyloP100

9.4

PrimateAI

Uncertain

0.73

PROVEAN

Pathogenic

-9.2

D;D;D

REVEL

Pathogenic

0.87

Sift

Pathogenic

0.0

D;D;D

Sift4G

Uncertain

0.041

D;D;D

Polyphen

1.0

D;.;.

Vest4

0.95

MutPred

0.83

Loss of disorder (P = 0.0521);.;Loss of disorder (P = 0.0521);

MVP

0.80

MPC

0.31

ClinPred

1.0

GERP RS

5.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.92

gMVP

0.87

Mutation Taster

=123/177

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

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

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over