Variant 9-122159666-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1PM2BP4_Moderate

The NM_014222.3(NDUFA8):c.12A>G(p.Ile4Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000137 in 1,461,830 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

NDUFA8
NM_014222.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.83

Variant links:

Genes affected

NDUFA8 (HGNC:7692): (NADH:ubiquinone oxidoreductase subunit A8) The protein encoded by this gene belongs to the complex I 19 kDa subunit family. Mammalian complex I is composed of 45 different subunits. This protein has NADH dehydrogenase activity and oxidoreductase activity. It plays an important role in transfering electrons from NADH to the respiratory chain. The immediate electron acceptor for the enzyme is believed to be ubiquinone. Alternative splicing of this gene results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Dec 2015]

NDUFA8 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM1

In a chain NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 8 (size 170) in uniprot entity NDUA8_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_014222.3

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.17106867).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NDUFA8	NM_014222.3 linkuse as main transcript	c.12A>G	p.Ile4Met	missense_variant	1/4	ENST00000373768.4
NDUFA8	NM_001318195.2 linkuse as main transcript	c.12A>G	p.Ile4Met	missense_variant	1/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NDUFA8	ENST00000373768.4 linkuse as main transcript	c.12A>G	p.Ile4Met	missense_variant	1/4	1	NM_014222.3	P1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251418

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135904

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 SAS 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:

0.0000137

AC:

AN:

1461830

Hom.:

Cov.:

AF XY:

0.0000165

AC XY:

AN XY:

727230

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000162

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000254

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 16, 2023

The c.12A>G (p.I4M) alteration is located in exon 1 (coding exon 1) of the NDUFA8 gene. This alteration results from a A to G substitution at nucleotide position 12, causing the isoleucine (I) at amino acid position 4 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.095

BayesDel_addAF

Benign

-0.030

BayesDel_noAF

Benign

-0.28

Cadd

Uncertain

Dann

Uncertain

0.99

DEOGEN2

Benign

0.16

Eigen

Benign

-0.075

Eigen_PC

Benign

0.083

FATHMM_MKL

Benign

0.63

LIST_S2

Benign

0.71

M_CAP

Benign

0.031

MetaRNN

Benign

0.17

MetaSVM

Benign

-0.81

MutationAssessor

Benign

1.1

MutationTaster

Benign

0.95

N;N

PrimateAI

Uncertain

0.53

PROVEAN

Benign

0.11

REVEL

Benign

0.27

Sift

Benign

0.073

Sift4G

Benign

0.17

Polyphen

0.65

Vest4

0.27

MutPred

0.25

Loss of catalytic residue at I4 (P = 0.0064);

MVP

0.94

MPC

0.41

ClinPred

0.59

GERP RS

3.8

RBP_binding_hub_radar

1.0

RBP_regulation_power_radar

2.7

Varity_R

0.55

gMVP

0.25

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over