Genetic Variant NARS2:p.Tyr138Tyr (chr11-78566231-A-G) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_024678.6(NARS2):c.414T>C(p.Tyr138Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.762 in 1,609,114 control chromosomes in the GnomAD database, including 471,876 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.71 ( 38909 hom., cov: 32)

Exomes 𝑓: 0.77 ( 432967 hom. )

Consequence

NARS2
NM_024678.6 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.0660

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.87).

BP6

Variant 11-78566231-A-G is Benign according to our data. Variant chr11-78566231-A-G is described in ClinVar as [Benign]. Clinvar id is 380001.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.066 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.786 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NARS2	NM_024678.6 link	c.414T>C	p.Tyr138Tyr	synonymous_variant	Exon 4 of 14	ENST00000281038.10	NP_078954.4	Q96I59-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NARS2	ENST00000281038.10 link	c.414T>C	p.Tyr138Tyr	synonymous_variant	Exon 4 of 14	1	NM_024678.6	ENSP00000281038.5		Q96I59-1

Frequencies

GnomAD3 genomes

AF:

0.710

AC:

107883

AN:

151956

Hom.:

38897

Cov.:

show subpopulations

Gnomad AFR

AF:

0.621

Gnomad AMI

AF:

0.795

Gnomad AMR

AF:

0.668

Gnomad ASJ

AF:

0.673

Gnomad EAS

AF:

0.568

Gnomad SAS

AF:

0.697

Gnomad FIN

AF:

0.677

Gnomad MID

AF:

0.674

Gnomad NFE

AF:

0.791

Gnomad OTH

AF:

0.713

GnomAD3 exomes

AF:

0.706

AC:

176150

AN:

249416

Hom.:

63403

AF XY:

0.715

AC XY:

96336

AN XY:

134778

show subpopulations

Gnomad AFR exome

AF:

0.617

Gnomad AMR exome

AF:

0.570

Gnomad ASJ exome

AF:

0.681

Gnomad EAS exome

AF:

0.569

Gnomad SAS exome

AF:

0.691

Gnomad FIN exome

AF:

0.691

Gnomad NFE exome

AF:

0.790

Gnomad OTH exome

AF:

0.734

GnomAD4 exome

AF:

0.768

AC:

1118321

AN:

1457040

Hom.:

432967

Cov.:

AF XY:

0.767

AC XY:

555654

AN XY:

724804

show subpopulations

Gnomad4 AFR exome

AF:

0.609

Gnomad4 AMR exome

AF:

0.580

Gnomad4 ASJ exome

AF:

0.676

Gnomad4 EAS exome

AF:

0.584

Gnomad4 SAS exome

AF:

0.684

Gnomad4 FIN exome

AF:

0.701

Gnomad4 NFE exome

AF:

0.800

Gnomad4 OTH exome

AF:

0.744

GnomAD4 genome

AF:

0.710

AC:

107937

AN:

152074

Hom.:

38909

Cov.:

AF XY:

0.703

AC XY:

52292

AN XY:

74358

show subpopulations

Gnomad4 AFR

AF:

0.620

Gnomad4 AMR

AF:

0.668

Gnomad4 ASJ

AF:

0.673

Gnomad4 EAS

AF:

0.567

Gnomad4 SAS

AF:

0.697

Gnomad4 FIN

AF:

0.677

Gnomad4 NFE

AF:

0.791

Gnomad4 OTH

AF:

0.715

Alfa

AF:

0.770

Hom.:

64710

Bravo

AF:

0.701

Asia WGS

AF:

0.668

AC:

2326

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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

- -

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. -

Combined oxidative phosphorylation defect type 24

Benign:1

Sep 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

4.3

DANN

Benign

0.35

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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

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