Genetic Variant NDUFAF8:p.Val7Leu (chr17-81239382-G-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001353403.1(NDUFAF8):c.-405G>C variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000246 in 1,218,188 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000025 ( 0 hom. )

Consequence

NDUFAF8
NM_001353403.1 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.02

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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.2168948).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001353403.1. 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.19G>C	p.Val7Leu	missense	Exon 1 of 3	NP_001079990.1	A1L188
NDUFAF8	NM_001353403.1		c.-405G>C		5_prime_UTR_premature_start_codon_gain	Exon 1 of 3	NP_001340332.1
NDUFAF8	NM_001353402.1		c.19G>C	p.Val7Leu	missense	Exon 1 of 3	NP_001340331.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NDUFAF8	ENST00000431388.3	TSL:1 MANE Select	c.19G>C	p.Val7Leu	missense	Exon 1 of 3	ENSP00000400184.2	A1L188
NDUFAF8	ENST00000577158.2	TSL:1	n.78G>C		non_coding_transcript_exon	Exon 1 of 3
NDUFAF8	ENST00000573090.1	TSL:3	n.72G>C		non_coding_transcript_exon	Exon 1 of 3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000246

AC:

AN:

1218188

Hom.:

Cov.:

AF XY:

0.00000341

AC XY:

AN XY:

587358

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

23488

American (AMR)

AF:

0.00

AC:

AN:

9790

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

16722

East Asian (EAS)

AF:

0.00

AC:

AN:

27336

South Asian (SAS)

AF:

0.00

AC:

AN:

51522

European-Finnish (FIN)

AF:

0.00

AC:

AN:

42802

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3370

European-Non Finnish (NFE)

AF:

0.00000302

AC:

AN:

993410

Other (OTH)

AF:

0.00

AC:

AN:

49748

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

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

Benign

0.29

BayesDel_addAF

Benign

0.011

BayesDel_noAF

Benign

-0.22

CADD

Benign

(source)

DANN

Benign

0.82

DEOGEN2

Benign

0.024

Eigen

Benign

-0.28

Eigen_PC

Benign

-0.22

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.58

M_CAP

Uncertain

0.28

MetaRNN

Benign

0.22

MetaSVM

Benign

-0.73

PhyloP100

2.0

PROVEAN

Benign

-1.4

REVEL

Benign

0.074

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

0.022

Vest4

0.23

MutPred

0.23

Loss of sheet (P = 0.0228)

MVP

0.040

MPC

0.23

ClinPred

0.86

GERP RS

3.8

PromoterAI

-0.028

Neutral

(source)

RBP_binding_hub_radar

1.0

RBP_regulation_power_radar

2.7

Varity_R

0.27

gMVP

0.51

Mutation Taster

=99/1

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

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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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over