11-78568744-T-G

Position:

• chr11-78568744-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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. 14/20 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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.90

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NARS2	NM_024678.6	c.260A>C	p.Asn87Thr	missense_variant	3/14	ENST00000281038.10	NP_078954.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NARS2	ENST00000281038.10	c.260A>C	p.Asn87Thr	missense_variant	3/14	1	NM_024678.6	ENSP00000281038.5

Frequencies

GnomAD3 genomes AF: 0.760 AC: 115489 AN: 151892 Hom.: 44212 Cov.: 32

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

GnomAD3 exomes AF: 0.727 AC: 181662 AN: 249758 Hom.: 67021 AF XY: 0.733 AC XY: 99009 AN XY: 135074

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 SAS exome AF: 0.713

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.: 30 AF XY: 0.777 AC XY: 560760 AN XY: 722062

Gnomad4 AFR exome AF: 0.777

Gnomad4 AMR exome AF: 0.593

Gnomad4 ASJ exome AF: 0.737

Gnomad4 EAS exome AF: 0.603

Gnomad4 SAS exome AF: 0.707

Gnomad4 FIN exome AF: 0.709

Gnomad4 NFE exome AF: 0.802

Gnomad4 OTH exome AF: 0.762

GnomAD4 genome AF: 0.760 AC: 115576 AN: 152010 Hom.: 44245 Cov.: 32 AF XY: 0.753 AC XY: 55994 AN XY: 74316

Gnomad4 AFR AF: 0.778

Gnomad4 AMR AF: 0.687

Gnomad4 ASJ AF: 0.740

Gnomad4 EAS AF: 0.588

Gnomad4 SAS AF: 0.723

Gnomad4 FIN AF: 0.684

Gnomad4 NFE AF: 0.795

Gnomad4 OTH AF: 0.757

Alfa AF: 0.783 Hom.: 109383

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

Submissions by phenotype

Combined oxidative phosphorylation defect type 24 Benign:2

Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Hearing loss, autosomal recessive 94 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 05, 2021

- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Dec 02, 2015

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	3.9
DANN	Benign	0.40
DEOGEN2	Benign	0.0085	T;T
Eigen	Benign	-0.97
Eigen_PC	Benign	-0.71
FATHMM_MKL	Benign	0.013	N
LIST_S2	Benign	0.0070	T;T
MetaRNN	Benign	8.7e-7	T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-1.9	N;.
PrimateAI	Benign	0.32	T
PROVEAN	Benign	1.5	N;N
REVEL	Benign	0.077
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;.
Polyphen		0.0	B;.
Vest4		0.025
MPC		0.046
ClinPred		0.0016	T
GERP RS		4.5
Varity_R		0.052
gMVP		0.18

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

Other links and lift over

dbSNP: rs10501429; hg19: chr11-78279790; COSMIC: COSV55250015; COSMIC: COSV55250015;