Genetic Variant NARS2:p.Asn87Ser (chr11-78568744-T-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_024678.6(NARS2):c.260A>G(p.Asn87Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N87T) has been classified as Benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

NARS2
NM_024678.6 missense

Scores

Clinical Significance

Not reported in ClinVar

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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.08136621).

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>G	p.Asn87Ser	missense	Exon 3 of 14	NP_078954.4
NARS2	NM_001425299.1		c.260A>G	p.Asn87Ser	missense	Exon 3 of 15	NP_001412228.1
NARS2	NM_001425300.1		c.260A>G	p.Asn87Ser	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>G	p.Asn87Ser	missense	Exon 3 of 14	ENSP00000281038.5
NARS2	ENST00000695360.1		c.260A>G	p.Asn87Ser	missense	Exon 3 of 14	ENSP00000511835.1
NARS2	ENST00000695344.1		c.260A>G	p.Asn87Ser	missense	Exon 3 of 12	ENSP00000511819.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1452262

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

722852

African (AFR)

AF:

0.00

AC:

AN:

33256

American (AMR)

AF:

0.00

AC:

AN:

44260

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25914

East Asian (EAS)

AF:

0.00

AC:

AN:

39578

South Asian (SAS)

AF:

0.00

AC:

AN:

85144

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53092

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5740

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1105282

Other (OTH)

AF:

0.00

AC:

AN:

59996

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.058

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.74

CADD

Benign

7.9

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.0086

Eigen

Benign

-0.71

Eigen_PC

Benign

-0.50

FATHMM_MKL

Uncertain

0.81

LIST_S2

Benign

0.073

M_CAP

Benign

0.0030

MetaRNN

Benign

0.081

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.81

PhyloP100

1.9

PrimateAI

Benign

0.30

PROVEAN

Benign

0.46

REVEL

Benign

0.041

Sift

Benign

0.52

Sift4G

Benign

0.53

Polyphen

0.0

Vest4

0.040

MutPred

0.34

Gain of phosphorylation at N87 (P = 0.013)

MVP

0.24

MPC

0.039

ClinPred

0.36

GERP RS

4.5

Varity_R

0.034

gMVP

0.13

Mutation Taster

=286/14

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over