Genetic Variant NDUFB8:c.85+36G>A (chr10-100529731-C-T) – ACMG Classification: Benign (-16 pts)

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_StrongBA1

The NM_005004.4(NDUFB8):c.85+36G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0112 in 1,601,534 control chromosomes in the GnomAD database, including 265 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.012 ( 38 hom., cov: 32)

Exomes 𝑓: 0.011 ( 227 hom. )

Consequence

NDUFB8
NM_005004.4 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.945

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 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: Benign. The variant received -16 ACMG points.

BP6

Variant 10-100529731-C-T is Benign according to our data. Variant chr10-100529731-C-T is described in ClinVar as Benign. ClinVar VariationId is 1264789.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0502 is higher than 0.05.

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	Effect	Exon Rank	Protein	UniProt
NDUFB8	NM_005004.4	MANE Select	c.85+36G>A	intron	N/A	NP_004995.1	O95169-1
NDUFB8	NM_001284367.2		c.85+36G>A	intron	N/A	NP_001271296.1	O95169-2
NDUFB8	NM_001284368.1		c.-9+127G>A	intron	N/A	NP_001271297.1	O95169-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
NDUFB8	ENST00000299166.9	TSL:1 MANE Select	c.85+36G>A	intron	N/A	ENSP00000299166.4	O95169-1
ENSG00000255339	ENST00000557395.5	TSL:2	n.85+36G>A	intron	N/A	ENSP00000456832.1
NDUFB8	ENST00000937696.1		c.85+36G>A	intron	N/A	ENSP00000607755.1

Frequencies

GnomAD3 genomes

AF:

0.0120

AC:

1822

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00205

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0529

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.000580

Gnomad SAS

AF:

0.00476

Gnomad FIN

AF:

0.0180

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00999

Gnomad OTH

AF:

0.0129

GnomAD2 exomes

AF:

0.0175

AC:

4233

AN:

242078

AF XY:

0.0146

show subpopulations

Gnomad AFR exome

AF:

0.00244

Gnomad AMR exome

AF:

0.0780

Gnomad ASJ exome

AF:

0.00186

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0202

Gnomad NFE exome

AF:

0.00894

Gnomad OTH exome

AF:

0.0153

GnomAD4 exome

AF:

0.0111

AC:

16156

AN:

1449214

Hom.:

227

Cov.:

AF XY:

0.0106

AC XY:

7651

AN XY:

720160

show subpopulations

African (AFR)

AF:

0.00187

AC:

AN:

33144

American (AMR)

AF:

0.0775

AC:

3344

AN:

43146

Ashkenazi Jewish (ASJ)

AF:

0.00225

AC:

AN:

25736

East Asian (EAS)

AF:

0.0000254

AC:

AN:

39420

South Asian (SAS)

AF:

0.00528

AC:

451

AN:

85346

European-Finnish (FIN)

AF:

0.0209

AC:

1066

AN:

51086

Middle Eastern (MID)

AF:

0.00175

AC:

AN:

5728

European-Non Finnish (NFE)

AF:

0.00951

AC:

10516

AN:

1105712

Other (OTH)

AF:

0.0108

AC:

648

AN:

59896

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

813

1626

2440

3253

4066

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

436

872

1308

1744

2180

<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

AF:

0.0120

AC:

1829

AN:

152320

Hom.:

Cov.:

AF XY:

0.0133

AC XY:

989

AN XY:

74470

show subpopulations

African (AFR)

AF:

0.00204

AC:

AN:

41578

American (AMR)

AF:

0.0533

AC:

815

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00144

AC:

AN:

3472

East Asian (EAS)

AF:

0.000582

AC:

AN:

5158

South Asian (SAS)

AF:

0.00476

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.0180

AC:

191

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00999

AC:

680

AN:

68042

Other (OTH)

AF:

0.0128

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

182

274

365

456

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00580

Hom.:

Bravo

AF:

0.0159

Asia WGS

AF:

0.00433

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.79

CADD

Benign

(source)

DANN

Benign

0.90

PhyloP100

0.94

PromoterAI

-0.034

Neutral

(source)

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.49

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.49

Position offset: -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

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over