11-78498833-G-A

Variant names:

• chr11-78498833-G-A
• rs11237522
• NM_024678.6:c.690-5638C>T

Variant summary

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

The NM_024678.6(NARS2):​c.690-5638C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.669 in 148,802 control chromosomes in the GnomAD database, including 35,649 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 0.67 (35649 hom., cov: 26)
• Consequence: NARS2 NM_024678.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.319
• Publications: 12 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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.808 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NARS2	NM_024678.6	c.690-5638C>T		intron_variant	Intron 6 of 13	ENST00000281038.10	NP_078954.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NARS2	ENST00000281038.10	c.690-5638C>T		intron_variant	Intron 6 of 13	1	NM_024678.6	ENSP00000281038.5

Frequencies

GnomAD3 genomes AF: 0.669 AC: 99450 AN: 148720 Hom.: 35647 Cov.: 26

Gnomad AFR AF: 0.402

Gnomad AMI AF: 0.834

Gnomad AMR AF: 0.687

Gnomad ASJ AF: 0.705

Gnomad EAS AF: 0.584

Gnomad SAS AF: 0.730

Gnomad FIN AF: 0.719

Gnomad MID AF: 0.701

Gnomad NFE AF: 0.814

Gnomad OTH AF: 0.687

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

GnomAD4 genome AF: 0.669 AC: 99487 AN: 148802 Hom.: 35649 Cov.: 26 AF XY: 0.664 AC XY: 48048 AN XY: 72308

African (AFR) AF: 0.402 AC: 16244 AN: 40410

American (AMR) AF: 0.687 AC: 10210 AN: 14852

Ashkenazi Jewish (ASJ) AF: 0.705 AC: 2441 AN: 3464

East Asian (EAS) AF: 0.584 AC: 2947 AN: 5050

South Asian (SAS) AF: 0.731 AC: 3477 AN: 4758

European-Finnish (FIN) AF: 0.719 AC: 6664 AN: 9274

Middle Eastern (MID) AF: 0.691 AC: 199 AN: 288

European-Non Finnish (NFE) AF: 0.814 AC: 55107 AN: 67708

Other (OTH) AF: 0.689 AC: 1439 AN: 2088

Alfa AF: 0.777 Hom.: 52683

Bravo AF: 0.652

Asia WGS AF: 0.667 AC: 2318 AN: 3472

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.40
DANN	Benign	0.51
PhyloP100		-0.32
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: rs11237522; hg19: chr11-78209879;