NM_024678.6:c.595-8415T>C

Variant names:

• chr11-78537351-A-G
• rs11237537
• NM_024678.6:c.595-8415T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_024678.6(NARS2):​c.595-8415T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.742 in 152,092 control chromosomes in the GnomAD database, including 42,421 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.74 (42421 hom., cov: 32)
• Consequence: NARS2 NM_024678.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.145
• Publications: 16 publications found

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

ENSG00000255084 (HGNC:58264):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.0).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.81 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NARS2	NM_024678.6	c.595-8415T>C		intron_variant	Intron 5 of 13	ENST00000281038.10	NP_078954.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NARS2	ENST00000281038.10	c.595-8415T>C		intron_variant	Intron 5 of 13	1	NM_024678.6	ENSP00000281038.5

Frequencies

GnomAD3 genomes AF: 0.743 AC: 112843 AN: 151974 Hom.: 42398 Cov.: 32

Gnomad AFR AF: 0.658

Gnomad AMI AF: 0.825

Gnomad AMR AF: 0.712

Gnomad ASJ AF: 0.757

Gnomad EAS AF: 0.593

Gnomad SAS AF: 0.741

Gnomad FIN AF: 0.712

Gnomad MID AF: 0.728

Gnomad NFE AF: 0.815

Gnomad OTH AF: 0.743

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.742 AC: 112907 AN: 152092 Hom.: 42421 Cov.: 32 AF XY: 0.737 AC XY: 54754 AN XY: 74326

African (AFR) AF: 0.658 AC: 27281 AN: 41476

American (AMR) AF: 0.712 AC: 10888 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.757 AC: 2624 AN: 3468

East Asian (EAS) AF: 0.592 AC: 3060 AN: 5168

South Asian (SAS) AF: 0.741 AC: 3570 AN: 4816

European-Finnish (FIN) AF: 0.712 AC: 7514 AN: 10558

Middle Eastern (MID) AF: 0.718 AC: 211 AN: 294

European-Non Finnish (NFE) AF: 0.815 AC: 55436 AN: 67996

Other (OTH) AF: 0.745 AC: 1571 AN: 2110

Alfa AF: 0.785 Hom.: 61190

Bravo AF: 0.737

Asia WGS AF: 0.701 AC: 2441 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	2.7
DANN	Benign	0.69
PhyloP100		0.14
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs11237537; hg19: chr11-78248397;