17-81239391-C-A

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP2PP3

The NM_001086521.2(NDUFAF8):c.28C>A(p.Arg10Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000165 in 1,215,742 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. R10C) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000016 ( 0 hom. )

Consequence

NDUFAF8
NM_001086521.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.16

Publications

0 publications found

Variant links:

Genes affected

NDUFAF8 (HGNC:33551): (NADH:ubiquinone oxidoreductase complex assembly factor 8) Involved in mitochondrial respiratory chain complex I assembly. Located in mitochondrion. Implicated in nuclear type mitochondrial complex I deficiency 34. [provided by Alliance of Genome Resources, Apr 2022]

NDUFAF8 Gene-Disease associations (from GenCC):

mitochondrial complex I deficiency, nuclear type 34
Inheritance: AR Classification: STRONG, MODERATE Submitted by: G2P, Ambry Genetics
Leigh syndrome
Inheritance: AR Classification: MODERATE Submitted by: ClinGen
mitochondrial complex I deficiency
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

NDUFAF8 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 1 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 0.3948 (below the threshold of 3.09). Trascript score misZ: -1.1983 (below the threshold of 3.09). GenCC associations: The gene is linked to mitochondrial complex I deficiency, nuclear type 34, mitochondrial complex I deficiency, Leigh syndrome.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.782

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001086521.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NDUFAF8	NM_001086521.2	MANE Select	c.28C>A	p.Arg10Ser	missense	Exon 1 of 3	NP_001079990.1	A1L188
NDUFAF8	NM_001353402.1		c.28C>A	p.Arg10Ser	missense	Exon 1 of 3	NP_001340331.1
NDUFAF8	NM_001353403.1		c.-396C>A		5_prime_UTR	Exon 1 of 3	NP_001340332.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NDUFAF8	ENST00000431388.3	TSL:1 MANE Select	c.28C>A	p.Arg10Ser	missense	Exon 1 of 3	ENSP00000400184.2	A1L188
NDUFAF8	ENST00000577158.2	TSL:1	n.87C>A		non_coding_transcript_exon	Exon 1 of 3
NDUFAF8	ENST00000573090.1	TSL:3	n.81C>A		non_coding_transcript_exon	Exon 1 of 3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000165

AC:

AN:

1215742

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

586084

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

23466

American (AMR)

AF:

0.00

AC:

AN:

9732

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

16666

East Asian (EAS)

AF:

0.00

AC:

AN:

27286

South Asian (SAS)

AF:

0.00

AC:

AN:

51096

European-Finnish (FIN)

AF:

0.0000235

AC:

AN:

42504

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3358

European-Non Finnish (NFE)

AF:

0.00000101

AC:

AN:

991952

Other (OTH)

AF:

0.00

AC:

AN:

49682

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000000770867), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.400

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.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.43

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Uncertain

0.010

CADD

Pathogenic

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.041

Eigen

Benign

0.14

Eigen_PC

Benign

0.14

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.61

M_CAP

Pathogenic

0.39

MetaRNN

Pathogenic

0.78

MetaSVM

Benign

-0.64

PhyloP100

4.2

PROVEAN

Benign

-2.3

REVEL

Benign

0.15

Sift

Benign

0.071

Sift4G

Benign

0.093

Polyphen

0.79

Vest4

0.76

MutPred

0.25

Loss of methylation at R10 (P = 0.0152)

MVP

0.17

MPC

0.87

ClinPred

0.90

GERP RS

3.8

PromoterAI

0.063

Neutral

(source)

RBP_binding_hub_radar

1.0

RBP_regulation_power_radar

2.7

Varity_R

0.29

gMVP

0.51

Mutation Taster

=95/5

polymorphism

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over