dbSNP rs4945276: NARS2:c.1165-10180A>C (chr11-78453938-T-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_024678.6(NARS2):c.1165-10180A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.24 in 152,142 control chromosomes in the GnomAD database, including 5,433 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 0.24 ( 5433 hom., cov: 32)

Consequence

NARS2
NM_024678.6 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.487

Publications

12 publications found

Variant links:

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

NARS2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.82).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.331 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NARS2	NM_024678.6 link	c.1165-10180A>C		intron_variant	Intron 11 of 13	ENST00000281038.10	NP_078954.4	Q96I59-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NARS2	ENST00000281038.10 link	c.1165-10180A>C		intron_variant	Intron 11 of 13	1	NM_024678.6	ENSP00000281038.5		Q96I59-1

Frequencies

GnomAD3 genomes

AF:

0.240

AC:

36549

AN:

152024

Hom.:

5435

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0753

Gnomad AMI

AF:

0.346

Gnomad AMR

AF:

0.279

Gnomad ASJ

AF:

0.331

Gnomad EAS

AF:

0.0857

Gnomad SAS

AF:

0.193

Gnomad FIN

AF:

0.273

Gnomad MID

AF:

0.326

Gnomad NFE

AF:

0.335

Gnomad OTH

AF:

0.277

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

GnomAD4 genome

AF:

0.240

AC:

36539

AN:

152142

Hom.:

5433

Cov.:

AF XY:

0.236

AC XY:

17593

AN XY:

74392

show subpopulations

African (AFR)

AF:

0.0751

AC:

3119

AN:

41542

American (AMR)

AF:

0.279

AC:

4259

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.331

AC:

1148

AN:

3464

East Asian (EAS)

AF:

0.0857

AC:

444

AN:

5178

South Asian (SAS)

AF:

0.194

AC:

934

AN:

4822

European-Finnish (FIN)

AF:

0.273

AC:

2889

AN:

10576

Middle Eastern (MID)

AF:

0.303

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.335

AC:

22764

AN:

67962

Other (OTH)

AF:

0.274

AC:

579

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1359

2718

4076

5435

6794

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

364

728

1092

1456

1820

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.306

Hom.:

14669

Bravo

AF:

0.236

Asia WGS

AF:

0.121

AC:

423

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

4.6

(source)

DANN

Benign

0.76

PhyloP100

0.49

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over