rs35462421

Positions:

chr2-240011654-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP3BP4_StrongBP6_Very_StrongBS1BS2

The NM_004544.4(NDUFA10):c.712G>A(p.Glu238Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00635 in 1,613,638 control chromosomes in the GnomAD database, including 48 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0057 ( 3 hom., cov: 32)

Exomes 𝑓: 0.0064 ( 45 hom. )

Consequence

NDUFA10
NM_004544.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 6.52

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 Benign. Variant got -19 ACMG points.

PP3

Multiple lines of computational evidence support a deleterious effect 8: AlphaMissense, BayesDel_addAF, BayesDel_noAF, Cadd, Dann, Eigen, MutationAssessor, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=0.016113639).

BP6

Variant 2-240011654-C-T is Benign according to our data. Variant chr2-240011654-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 138437.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0057 (868/152294) while in subpopulation AMR AF= 0.00941 (144/15300). AF 95% confidence interval is 0.00838. There are 3 homozygotes in gnomad4. There are 397 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NDUFA10	NM_004544.4 linkuse as main transcript	c.712G>A	p.Glu238Lys	missense_variant	6/10	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.712G>A	p.Glu238Lys	missense_variant	6/10	1	NM_004544.4	ENSP00000252711.2		O95299-1

Frequencies

GnomAD3 genomes

AF:

0.00570

AC:

868

AN:

152176

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00128

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00942

Gnomad ASJ

AF:

0.00461

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00455

Gnomad FIN

AF:

0.000283

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.00895

Gnomad OTH

AF:

0.00861

GnomAD3 exomes

AF:

0.00579

AC:

1456

AN:

251482

Hom.:

AF XY:

0.00601

AC XY:

817

AN XY:

135908

show subpopulations

Gnomad AFR exome

AF:

0.000738

Gnomad AMR exome

AF:

0.00893

Gnomad ASJ exome

AF:

0.00526

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00402

Gnomad FIN exome

AF:

0.000878

Gnomad NFE exome

AF:

0.00777

Gnomad OTH exome

AF:

0.00896

GnomAD4 exome

AF:

0.00642

AC:

9384

AN:

1461344

Hom.:

Cov.:

AF XY:

0.00644

AC XY:

4684

AN XY:

727014

show subpopulations

Gnomad4 AFR exome

AF:

0.000687

Gnomad4 AMR exome

AF:

0.00890

Gnomad4 ASJ exome

AF:

0.00490

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00422

Gnomad4 FIN exome

AF:

0.00125

Gnomad4 NFE exome

AF:

0.00711

Gnomad4 OTH exome

AF:

0.00750

GnomAD4 genome

AF:

0.00570

AC:

868

AN:

152294

Hom.:

Cov.:

AF XY:

0.00533

AC XY:

397

AN XY:

74462

show subpopulations

Gnomad4 AFR

AF:

0.00127

Gnomad4 AMR

AF:

0.00941

Gnomad4 ASJ

AF:

0.00461

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00456

Gnomad4 FIN

AF:

0.000283

Gnomad4 NFE

AF:

0.00897

Gnomad4 OTH

AF:

0.00852

Alfa

AF:

0.00783

Hom.:

Bravo

AF:

0.00639

TwinsUK

AF:

0.00674

AC:

ALSPAC

AF:

0.00752

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00802

AC:

ExAC

AF:

0.00535

AC:

650

Asia WGS

AF:

0.00231

AC:

AN:

3478

EpiCase

AF:

0.0104

EpiControl

AF:

0.00936

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	NDUFA10: BS2 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	May 11, 2017	- -

Leigh syndrome

Benign:3

Benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The NDUFA10 p.E238K variant was not identified in the literature but was identified in dbSNP (ID: rs35462421) and ClinVar (classified as likely benign by Invitae and three other laboratories; and as benign by GeneDx and Illumina). The variant was identified in control databases in 1601 of 282886 chromosomes (7 homozygous) at a frequency of 0.005660, and was observed at the highest frequency in the European (non-Finnish) population in 1009 of 129192 chromosomes (5 homozygous) (freq: 0.007810) (Genome Aggregation Database March 6, 2019, v2.1.1). The p.E238 residue is conserved in mammals and computational analyses (MUT Assesor, PolyPhen-2, SIFT, MutationTaster, Revel, FATHMM, MetaLR, DANN) suggest that the variant may impact the protein; however this is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (Splice AI exome) do not predict a difference in splicing. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -
Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Apr 07, 2014

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Mitochondrial complex 1 deficiency, nuclear type 22

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Feb 07, 2022

- -

Mitochondrial complex I deficiency, nuclear type 1

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.66

BayesDel_addAF

Pathogenic

0.20

BayesDel_noAF

Pathogenic

0.52

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.64

.;D;.;.;.;.

Eigen

Pathogenic

0.78

Eigen_PC

Pathogenic

0.69

FATHMM_MKL

Uncertain

0.96

MetaRNN

Benign

0.015

T;T;T;T;T;T

MetaSVM

Pathogenic

0.91

MutationAssessor

Pathogenic

3.3

.;M;.;.;.;.

PrimateAI

Uncertain

0.50

PROVEAN

Uncertain

-3.4

D;D;D;.;D;D

REVEL

Pathogenic

0.94

Sift

Uncertain

0.0040

D;D;D;.;D;D

Sift4G

Pathogenic

0.0

D;D;D;D;D;D

Polyphen

1.0

.;D;.;.;.;.

Vest4

0.85, 0.84, 0.85, 0.81

MVP

1.0

MPC

0.68

ClinPred

0.032

GERP RS

4.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.85

gMVP

0.69

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.10

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