11-78491342-C-T

Variant names:

• chr11-78491342-C-T
• rs7395344
• NM_024678.6:c.822+1721G>A

Variant summary

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

The NM_001425299.1(NARS2):​c.822+1721G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.752 in 152,168 control chromosomes in the GnomAD database, including 43,413 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 0.75 (43413 hom., cov: 34)
• Consequence: NARS2 NM_001425299.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.340
• Publications: 9 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

LOC105369403 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.809 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001425299.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NARS2	NM_024678.6	MANE Select	c.822+1721G>A		intron	N/A	NP_078954.4
	NARS2	NM_001425299.1		c.822+1721G>A		intron	N/A	NP_001412228.1
	NARS2	NM_001425300.1		c.822+1721G>A		intron	N/A	NP_001412229.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NARS2	ENST00000281038.10	TSL:1 MANE Select	c.822+1721G>A		intron	N/A	ENSP00000281038.5
	NARS2	ENST00000695360.1		c.822+1721G>A		intron	N/A	ENSP00000511835.1
	NARS2	ENST00000695344.1		c.741+1721G>A		intron	N/A	ENSP00000511819.1

Frequencies

GnomAD3 genomes AF: 0.752 AC: 114276 AN: 152050 Hom.: 43386 Cov.: 34

Gnomad AFR AF: 0.695

Gnomad AMI AF: 0.835

Gnomad AMR AF: 0.718

Gnomad ASJ AF: 0.705

Gnomad EAS AF: 0.585

Gnomad SAS AF: 0.735

Gnomad FIN AF: 0.711

Gnomad MID AF: 0.725

Gnomad NFE AF: 0.815

Gnomad OTH AF: 0.751

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

GnomAD4 genome AF: 0.752 AC: 114363 AN: 152168 Hom.: 43413 Cov.: 34 AF XY: 0.745 AC XY: 55449 AN XY: 74384

African (AFR) AF: 0.695 AC: 28862 AN: 41502

American (AMR) AF: 0.718 AC: 10984 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.705 AC: 2446 AN: 3470

East Asian (EAS) AF: 0.584 AC: 3015 AN: 5160

South Asian (SAS) AF: 0.735 AC: 3550 AN: 4830

European-Finnish (FIN) AF: 0.711 AC: 7530 AN: 10584

Middle Eastern (MID) AF: 0.711 AC: 209 AN: 294

European-Non Finnish (NFE) AF: 0.815 AC: 55418 AN: 68006

Other (OTH) AF: 0.752 AC: 1589 AN: 2112

Alfa AF: 0.773 Hom.: 19471

Bravo AF: 0.749

Asia WGS AF: 0.697 AC: 2428 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.66
DANN	Benign	0.49
PhyloP100		-0.34
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: rs7395344; hg19: chr11-78202388;