rs199842745

Positions:

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_175614.5(NDUFA11):c.311G>T(p.Arg104Leu) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000881 in 1,570,574 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00051 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00092 ( 1 hom. )

Consequence

NDUFA11
NM_175614.5 missense, splice_region

Scores

Splicing: ADA: 0.6321

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:1

Conservation

PhyloP100: 5.90

Variant links:

Genes affected

NDUFA11 (HGNC:20371): (NADH:ubiquinone oxidoreductase subunit A11) This gene encodes a subunit of the membrane-bound mitochondrial complex I. Complex I is composed of numerous subunits and functions as the NADH-ubiquinol reductase of the mitochondrial electron transport chain. Mutations in this gene are associated with severe mitochondrial complex I deficiency. Alternate splicing results in multiple transcript variants.[provided by RefSeq, Oct 2010]

NDUFA11 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.08424276).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
NDUFA11	NM_175614.5 linkuse as main transcript	c.311G>T	p.Arg104Leu	missense_variant, splice_region_variant	3/4	ENST00000308961.5	NP_783313.1
NDUFA11	NM_001193375.3 linkuse as main transcript	c.311G>T	p.Arg104Leu	missense_variant, splice_region_variant	3/4		NP_001180304.1
NDUFA11	NR_034166.3 linkuse as main transcript	n.513G>T		splice_region_variant, non_coding_transcript_exon_variant	4/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NDUFA11	ENST00000308961.5 linkuse as main transcript	c.311G>T	p.Arg104Leu	missense_variant, splice_region_variant	3/4	1	NM_175614.5	ENSP00000311740	P1	Q86Y39-1

Frequencies

GnomAD3 genomes

AF:

0.000507

AC:

AN:

152012

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00375

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000750

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000702

AC:

128

AN:

182298

Hom.:

AF XY:

0.000728

AC XY:

AN XY:

97516

show subpopulations

Gnomad AFR exome

AF:

0.000279

Gnomad AMR exome

AF:

0.0000757

Gnomad ASJ exome

AF:

0.00517

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000286

Gnomad FIN exome

AF:

0.000124

Gnomad NFE exome

AF:

0.000849

Gnomad OTH exome

AF:

0.000826

GnomAD4 exome

AF:

0.000921

AC:

1307

AN:

1418444

Hom.:

Cov.:

AF XY:

0.000940

AC XY:

659

AN XY:

701126

show subpopulations

Gnomad4 AFR exome

AF:

0.000182

Gnomad4 AMR exome

AF:

0.0000804

Gnomad4 ASJ exome

AF:

0.00704

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000210

Gnomad4 FIN exome

AF:

0.000201

Gnomad4 NFE exome

AF:

0.000955

Gnomad4 OTH exome

AF:

0.000868

GnomAD4 genome

AF:

0.000506

AC:

AN:

152130

Hom.:

Cov.:

AF XY:

0.000444

AC XY:

AN XY:

74366

show subpopulations

Gnomad4 AFR

AF:

0.000169

Gnomad4 AMR

AF:

0.000262

Gnomad4 ASJ

AF:

0.00375

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000942

Gnomad4 NFE

AF:

0.000750

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000974

Hom.:

Bravo

AF:

0.000582

ESP6500AA

AF:

0.000231

AC:

ESP6500EA

AF:

0.00141

AC:

ExAC

AF:

0.000450

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2022	NDUFA11: PM2:Supporting -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Oct 08, 2019	Has not been previously published as pathogenic or benign to our knowledge; In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Mitochondrial complex I deficiency, nuclear type 1

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.72

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.10

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.26

.;.;T

Eigen

Uncertain

0.49

Eigen_PC

Uncertain

0.36

FATHMM_MKL

Benign

0.46

LIST_S2

Benign

0.36

T;T;T

M_CAP

Uncertain

0.24

MetaRNN

Benign

0.058

T;T;T

MetaSVM

Benign

-0.58

MutationAssessor

Uncertain

2.8

M;.;M

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Uncertain

0.57

PROVEAN

Benign

-2.1

N;.;D

REVEL

Uncertain

0.35

Sift

Uncertain

0.011

D;.;D

Sift4G

Uncertain

0.0090

D;D;D

Polyphen

1.0

.;.;D

Vest4

0.92

MVP

0.50

MPC

0.25

ClinPred

0.28

GERP RS

4.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.52

gMVP

0.74

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.63

dbscSNV1_RF

Benign

0.67

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