19-5893110-G-A

Position:

chr19-5893110-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001193375.3(NDUFA11):c.494C>T(p.Ala165Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000139 in 1,535,958 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00015 ( 0 hom. )

Consequence

NDUFA11
NM_001193375.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: -1.40

Variant links:

Genes affected

ENSG00000267740 (HGNC:):

ENSG00000267740 links:

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 Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.0051163435).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NDUFA11	NM_001193375.3 linkuse as main transcript	c.494C>T	p.Ala165Val	missense_variant	4/4		NP_001180304.1	Q86Y39-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	Protein	UniProt
ENSG00000267740	ENST00000586349.5 linkuse as main transcript	c.382+3343C>T		intron_variant		2	ENSP00000466639.1	K7EMT4
NDUFA11	ENST00000418389.6 linkuse as main transcript	c.494C>T	p.Ala165Val	missense_variant	4/4	2	ENSP00000389160.1	Q86Y39-2
ENSG00000267740	ENST00000585661.1 linkuse as main transcript	c.307+3343C>T		intron_variant		2	ENSP00000467210.1	K7EP35
ENSG00000267740	ENST00000592091.5 linkuse as main transcript	n.313+3343C>T		intron_variant		2	ENSP00000465499.1	K7EK78

Frequencies

GnomAD3 genomes

AF:

0.0000592

AC:

AN:

152106

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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:

0.0000882

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000732

AC:

AN:

136598

Hom.:

AF XY:

0.0000808

AC XY:

AN XY:

74294

show subpopulations

Gnomad AFR exome

AF:

0.000155

Gnomad AMR exome

AF:

0.0000818

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:

0.0000934

Gnomad OTH exome

AF:

0.000477

GnomAD4 exome

AF:

0.000147

AC:

204

AN:

1383852

Hom.:

Cov.:

AF XY:

0.000158

AC XY:

108

AN XY:

682864

show subpopulations

Gnomad4 AFR exome

AF:

0.000538

Gnomad4 AMR exome

AF:

0.0000560

Gnomad4 ASJ exome

AF:

0.0000397

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000126

Gnomad4 FIN exome

AF:

0.0000590

Gnomad4 NFE exome

AF:

0.000151

Gnomad4 OTH exome

AF:

0.000207

GnomAD4 genome

AF:

0.0000592

AC:

AN:

152106

Hom.:

Cov.:

AF XY:

0.0000807

AC XY:

AN XY:

74306

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000304

Hom.:

Bravo

AF:

0.000102

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000778

AC:

ExAC

AF:

0.000100

AC:

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 16, 2021

The c.494C>T (p.A165V) alteration is located in exon 4 (coding exon 4) of the NDUFA11 gene. This alteration results from a C to T substitution at nucleotide position 494, causing the alanine (A) at amino acid position 165 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Mitochondrial complex 1 deficiency, nuclear type 14

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Aug 28, 2019

A heterozygous missense variant was identified, NM_001193375.1(NDUFA11):c.494C>T in exon 4 of 4 of the NDUFA11 gene (NB: This variant is non-coding in the predominant alternative transcript, NM_175614.4). This substitution is predicted to create a minor amino acid change from alanine to valine at position 165 of the protein, NP_001180304.1(NDUFA11):p.(Ala165Val). The alanine at this position has low conservation (100 vertebrates, UCSC), and is not situated in a known functional domain. In silico software predictions of the pathogenicity of this variant are conflicting (Polyphen, SIFT, CADD, Mutation Taster). The variant is present in the gnomAD population database at a frequency of 0.0083% (14 heterozygotes, 0 homozygotes). The variant has been previously reported in a clinical testing setting. Based on information available at the time of curation, this variant has been classified as a VARIANT of UNCERTAIN SIGNIFICANCE (VUS) with LOW CLINICAL RELEVANCE. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.72

CADD

Benign

1.4

DANN

Uncertain

0.98

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.0017

LIST_S2

Benign

0.29

M_CAP

Benign

0.00096

MetaRNN

Benign

0.0051

MetaSVM

Benign

-1.0

PrimateAI

Benign

0.25

PROVEAN

Benign

0.030

REVEL

Benign

0.13

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0080

Vest4

0.044

MutPred

0.17

Gain of sheet (P = 0.0221);

MVP

0.043

MPC

0.20

ClinPred

0.0070

GERP RS

-1.3

gMVP

0.041

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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