11-78504036-A-T

Variant names:

• chr11-78504036-A-T
• rs7950813
• NM_024678.6:c.690-10841T>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.690-10841T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.687 in 152,074 control chromosomes in the GnomAD database, including 37,632 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 0.69 (37632 hom., cov: 32)
• Consequence: NARS2 NM_024678.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.597
• Publications: 11 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=-0.84).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.809 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NARS2	NM_024678.6	c.690-10841T>A		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.690-10841T>A		intron_variant	Intron 6 of 13	1	NM_024678.6	ENSP00000281038.5

Frequencies

GnomAD3 genomes AF: 0.688 AC: 104495 AN: 151956 Hom.: 37626 Cov.: 32

Gnomad AFR AF: 0.474

Gnomad AMI AF: 0.834

Gnomad AMR AF: 0.693

Gnomad ASJ AF: 0.693

Gnomad EAS AF: 0.583

Gnomad SAS AF: 0.736

Gnomad FIN AF: 0.712

Gnomad MID AF: 0.715

Gnomad NFE AF: 0.815

Gnomad OTH AF: 0.698

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

GnomAD4 genome AF: 0.687 AC: 104539 AN: 152074 Hom.: 37632 Cov.: 32 AF XY: 0.683 AC XY: 50799 AN XY: 74352

African (AFR) AF: 0.474 AC: 19639 AN: 41456

American (AMR) AF: 0.692 AC: 10582 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.693 AC: 2407 AN: 3472

East Asian (EAS) AF: 0.583 AC: 3006 AN: 5160

South Asian (SAS) AF: 0.736 AC: 3548 AN: 4818

European-Finnish (FIN) AF: 0.712 AC: 7519 AN: 10562

Middle Eastern (MID) AF: 0.701 AC: 206 AN: 294

European-Non Finnish (NFE) AF: 0.815 AC: 55392 AN: 68004

Other (OTH) AF: 0.701 AC: 1481 AN: 2114

Alfa AF: 0.674 Hom.: 2409

Bravo AF: 0.676

Asia WGS AF: 0.676 AC: 2355 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	7.2
DANN	Benign	0.82
PhyloP100		0.60
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: rs7950813; hg19: chr11-78215082;