rs387906872

Positions:

chr2-240025301-T-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate

The NM_004544.4(NDUFA10):c.1A>G(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000113 in 1,504,940 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

NDUFA10
NM_004544.4 start_lost

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 1.09

Variant links:

Genes affected

NDUFA10 (HGNC:7684): (NADH:ubiquinone oxidoreductase subunit A10) The protein encoded by this gene is a component of 42 kDa complex I, the first enzyme complex in the electron transport chain of mitochondria. This protein has NADH dehydrogenase activity and oxidoreductase activity. It transfers electrons from NADH to the respiratory chain. A mutation in this gene was found in an individual with Leigh syndrome. [provided by RefSeq, Apr 2016]

NDUFA10 links:

NDUFA10 (HGNC:):

NDUFA10 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PVS1

Start lost variant, no new inframe start found.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 2-240025301-T-C is Pathogenic according to our data. Variant chr2-240025301-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 30392.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NDUFA10	NM_004544.4 linkuse as main transcript	c.1A>G	p.Met1?	start_lost	1/10	ENST00000252711.7	NP_004535.1	O95299-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NDUFA10	ENST00000252711.7 linkuse as main transcript	c.1A>G	p.Met1?	start_lost	1/10	1	NM_004544.4	ENSP00000252711.2		O95299-1

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

151830

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000289

AC:

AN:

103762

Hom.:

AF XY:

0.0000518

AC XY:

AN XY:

57936

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000106

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000540

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000111

AC:

AN:

1353110

Hom.:

Cov.:

AF XY:

0.0000165

AC XY:

AN XY:

667618

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000657

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000133

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000104

Gnomad4 OTH exome

AF:

0.0000179

GnomAD4 genome

AF:

0.0000132

AC:

AN:

151830

Hom.:

Cov.:

AF XY:

0.0000270

AC XY:

AN XY:

74152

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000264

ExAC

AF:

0.0000336

AC:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Mitochondrial complex 1 deficiency, nuclear type 22

Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 01, 2011	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 19, 2022	Variant summary: NDUFA10 c.1A>G (p.Met1?, aka p.Met1Val) alters the initiation codon and is predicted to result either in absence of the protein or truncation/extension of the encoded protein due to translation initiation at a downstream/upstream codon. No upstream in-frame ATG triplets were found that could generate an N-terminally extended protein product, and although a downstream in-frame ATG triplet was found, (i.e. Met40 in Exon 2), the utilization of Met40 as a start codon would result in an N-terminally truncated protein product, with the loss of the mitochondrial targeting signal (i.e. the 35 N-terminal amino acids; see Dang_2020). The variant allele was found at a frequency of 2.9e-05 in 103762 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant, c.1A>G, has been reported in the literature in a compound heterozygous individual affected with Mitochondrial Complex 1 Deficiency, Nuclear Type 22 (Hoefs_2011), and the authors of this study described a marked decrease of complex I activity in patient derived fibroblasts and muscle tissue, together with a strongly decreased NDUFA10 protein level on Western blot analysis. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.22

BayesDel_noAF

Pathogenic

0.29

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.080

T;.;.;.;.;T

Eigen

Benign

-0.0012

Eigen_PC

Benign

-0.16

FATHMM_MKL

Benign

0.020

M_CAP

Pathogenic

0.98

MetaRNN

Pathogenic

0.98

D;D;D;D;D;D

MetaSVM

Uncertain

0.10

PROVEAN

Benign

-1.5

N;N;.;N;N;N

REVEL

Uncertain

0.62

Sift

Pathogenic

0.0

D;D;.;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;.;D;D

Polyphen

0.98

D;.;.;.;.;P

Vest4

0.58

MutPred

0.91

Loss of disorder (P = 0.1177);Loss of disorder (P = 0.1177);Loss of disorder (P = 0.1177);Loss of disorder (P = 0.1177);Loss of disorder (P = 0.1177);Loss of disorder (P = 0.1177);

MVP

0.86

ClinPred

0.98

GERP RS

3.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.96

gMVP

0.74

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