11-78450406-A-T

Variant names:

• chr11-78450406-A-T
• rs12287010
• NM_024678.6:c.1165-6648T>A

Variant summary

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

The NM_024678.6(NARS2):​c.1165-6648T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.225 in 152,028 control chromosomes in the GnomAD database, including 4,181 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 0.22 (4181 hom., cov: 31)
• Consequence: NARS2 NM_024678.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.224
• Publications: 5 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=-0.94).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.4 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NARS2	NM_024678.6	c.1165-6648T>A		intron_variant	Intron 11 of 13	ENST00000281038.10	NP_078954.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NARS2	ENST00000281038.10	c.1165-6648T>A		intron_variant	Intron 11 of 13	1	NM_024678.6	ENSP00000281038.5

Frequencies

GnomAD3 genomes AF: 0.225 AC: 34173 AN: 151910 Hom.: 4180 Cov.: 31

Gnomad AFR AF: 0.221

Gnomad AMI AF: 0.176

Gnomad AMR AF: 0.272

Gnomad ASJ AF: 0.295

Gnomad EAS AF: 0.414

Gnomad SAS AF: 0.280

Gnomad FIN AF: 0.290

Gnomad MID AF: 0.269

Gnomad NFE AF: 0.185

Gnomad OTH AF: 0.233

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

GnomAD4 genome AF: 0.225 AC: 34200 AN: 152028 Hom.: 4181 Cov.: 31 AF XY: 0.231 AC XY: 17171 AN XY: 74304

African (AFR) AF: 0.221 AC: 9156 AN: 41456

American (AMR) AF: 0.272 AC: 4163 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.295 AC: 1025 AN: 3470

East Asian (EAS) AF: 0.415 AC: 2140 AN: 5162

South Asian (SAS) AF: 0.280 AC: 1349 AN: 4824

European-Finnish (FIN) AF: 0.290 AC: 3059 AN: 10548

Middle Eastern (MID) AF: 0.282 AC: 83 AN: 294

European-Non Finnish (NFE) AF: 0.185 AC: 12578 AN: 67974

Other (OTH) AF: 0.231 AC: 487 AN: 2108

Alfa AF: 0.210 Hom.: 433

Bravo AF: 0.224

Asia WGS AF: 0.300 AC: 1040 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	7.2
DANN	Benign	0.83
PhyloP100		0.22
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: rs12287010; hg19: chr11-78161452;