chr11-78568744-T-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_024678.6(NARS2):c.260A>C(p.Asn87Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.776 in 1,602,524 control chromosomes in the GnomAD database, including 485,488 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.76 ( 44245 hom., cov: 32)

Exomes 𝑓: 0.78 ( 441243 hom. )

Consequence

NARS2
NM_024678.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 1.90

Publications

53 publications found

Variant links:

Genes affected

NARS2 (HGNC:26274): (asparaginyl-tRNA synthetase 2, mitochondrial) This gene encodes a putative member of the class II family of aminoacyl-tRNA synthetases. These enzymes play a critical role in protein biosynthesis by charging tRNAs with their cognate amino acids. This protein is encoded by the nuclear genome but is likely to be imported to the mitochondrion where it is thought to catalyze the ligation of asparagine to tRNA molecules. Mutations in this gene have been associated with combined oxidative phosphorylation deficiency 24 (COXPD24). [provided by RefSeq, Mar 2015]

NARS2 Gene-Disease associations (from GenCC):

combined oxidative phosphorylation defect type 24
Inheritance: AR, AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: PanelApp Australia, Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
mitochondrial disease
Inheritance: AR Classification: MODERATE Submitted by: Illumina
hearing loss, autosomal recessive
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
hearing loss, autosomal recessive 94
Inheritance: AR Classification: LIMITED Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae)
Leigh syndrome
Inheritance: AR Classification: LIMITED Submitted by: ClinGen
nonsyndromic genetic hearing loss
Inheritance: AR Classification: LIMITED Submitted by: ClinGen

NARS2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=8.725515E-7).

BP6

Variant 11-78568744-T-G is Benign according to our data. Variant chr11-78568744-T-G is described in ClinVar as Benign. ClinVar VariationId is 380000.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.789 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024678.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
NARS2	NM_024678.6	MANE Select	c.260A>C	p.Asn87Thr	missense	Exon 3 of 14	NP_078954.4
NARS2	NM_001425299.1		c.260A>C	p.Asn87Thr	missense	Exon 3 of 15	NP_001412228.1
NARS2	NM_001425300.1		c.260A>C	p.Asn87Thr	missense	Exon 3 of 13	NP_001412229.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
NARS2	ENST00000281038.10	TSL:1 MANE Select	c.260A>C	p.Asn87Thr	missense	Exon 3 of 14	ENSP00000281038.5
NARS2	ENST00000695360.1		c.260A>C	p.Asn87Thr	missense	Exon 3 of 14	ENSP00000511835.1
NARS2	ENST00000695344.1		c.260A>C	p.Asn87Thr	missense	Exon 3 of 12	ENSP00000511819.1

Frequencies

GnomAD3 genomes

AF:

0.760

AC:

115489

AN:

151892

Hom.:

44212

Cov.:

show subpopulations

Gnomad AFR

AF:

0.778

Gnomad AMI

AF:

0.796

Gnomad AMR

AF:

0.687

Gnomad ASJ

AF:

0.740

Gnomad EAS

AF:

0.589

Gnomad SAS

AF:

0.723

Gnomad FIN

AF:

0.684

Gnomad MID

AF:

0.715

Gnomad NFE

AF:

0.795

Gnomad OTH

AF:

0.756

GnomAD2 exomes

AF:

0.727

AC:

181662

AN:

249758

AF XY:

0.733

show subpopulations

Gnomad AFR exome

AF:

0.774

Gnomad AMR exome

AF:

0.584

Gnomad ASJ exome

AF:

0.740

Gnomad EAS exome

AF:

0.585

Gnomad FIN exome

AF:

0.699

Gnomad NFE exome

AF:

0.793

Gnomad OTH exome

AF:

0.750

GnomAD4 exome

AF:

0.778

AC:

1127921

AN:

1450514

Hom.:

441243

Cov.:

AF XY:

0.777

AC XY:

560760

AN XY:

722062

show subpopulations

African (AFR)

AF:

0.777

AC:

25788

AN:

33210

American (AMR)

AF:

0.593

AC:

26244

AN:

44230

Ashkenazi Jewish (ASJ)

AF:

0.737

AC:

19084

AN:

25896

East Asian (EAS)

AF:

0.603

AC:

23854

AN:

39552

South Asian (SAS)

AF:

0.707

AC:

60093

AN:

85052

European-Finnish (FIN)

AF:

0.709

AC:

37612

AN:

53062

Middle Eastern (MID)

AF:

0.669

AC:

3833

AN:

5730

European-Non Finnish (NFE)

AF:

0.802

AC:

885739

AN:

1103844

Other (OTH)

AF:

0.762

AC:

45674

AN:

59938

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

11043

22087

33130

44174

55217

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

20614

41228

61842

82456

103070

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.760

AC:

115576

AN:

152010

Hom.:

44245

Cov.:

AF XY:

0.753

AC XY:

55994

AN XY:

74316

show subpopulations

African (AFR)

AF:

0.778

AC:

32227

AN:

41444

American (AMR)

AF:

0.687

AC:

10480

AN:

15262

Ashkenazi Jewish (ASJ)

AF:

0.740

AC:

2568

AN:

3468

East Asian (EAS)

AF:

0.588

AC:

3032

AN:

5154

South Asian (SAS)

AF:

0.723

AC:

3490

AN:

4826

European-Finnish (FIN)

AF:

0.684

AC:

7217

AN:

10556

Middle Eastern (MID)

AF:

0.704

AC:

207

AN:

294

European-Non Finnish (NFE)

AF:

0.795

AC:

54039

AN:

67994

Other (OTH)

AF:

0.757

AC:

1593

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1413

2826

4239

5652

7065

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

858

1716

2574

3432

4290

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.782

Hom.:

193688

Bravo

AF:

0.757

TwinsUK

AF:

0.803

AC:

2976

ALSPAC

AF:

0.807

AC:

3111

ESP6500AA

AF:

0.780

AC:

3430

ESP6500EA

AF:

0.796

AC:

6835

ExAC

AF:

0.738

AC:

89583

Asia WGS

AF:

0.701

AC:

2436

AN:

3472

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Combined oxidative phosphorylation defect type 24

Benign:2

Sep 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

May 28, 2019

Mendelics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not specified

Benign:1

Dec 02, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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.

Hearing loss, autosomal recessive 94

Benign:1

Sep 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.064

BayesDel_addAF

Benign

-0.70

BayesDel_noAF

Benign

-0.63

CADD

Benign

3.9

(source)

DANN

Benign

0.40

DEOGEN2

Benign

0.0085

Eigen

Benign

-0.97

Eigen_PC

Benign

-0.71

FATHMM_MKL

Benign

0.013

LIST_S2

Benign

0.0070

MetaRNN

Benign

8.7e-7

MetaSVM

Benign

-0.96

MutationAssessor

Benign

-1.9

PhyloP100

1.9

PrimateAI

Benign

0.32

PROVEAN

Benign

1.5

REVEL

Benign

0.077

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.025

MPC

0.046

ClinPred

0.0016

GERP RS

4.5

Varity_R

0.052

gMVP

0.18

Mutation Taster

=286/14

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over