6-44306384-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_020745.4(AARS2):​c.1196A>C​(p.Asn399Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,870 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)
Exomes š‘“: 6.8e-7 ( 0 hom. )

Consequence

AARS2
NM_020745.4 missense

Scores

3
16

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -2.00
Variant links:
Genes affected
AARS2 (HGNC:21022): (alanyl-tRNA synthetase 2, mitochondrial) The protein encoded by this gene belongs to the class-II aminoacyl-tRNA synthetase family. Aminoacyl-tRNA synthetases play critical roles in mRNA translation by charging tRNAs with their cognate amino acids. The encoded protein is a mitochondrial enzyme that specifically aminoacylates alanyl-tRNA. Mutations in this gene are a cause of combined oxidative phosphorylation deficiency 8. [provided by RefSeq, Dec 2011]
TMEM151B (HGNC:21315): (transmembrane protein 151B) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.28743052).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
AARS2NM_020745.4 linkc.1196A>C p.Asn399Thr missense_variant Exon 9 of 22 ENST00000244571.5 NP_065796.2 Q5JTZ9
AARS2XM_005249245.4 linkc.905A>C p.Asn302Thr missense_variant Exon 7 of 20 XP_005249302.1
AARS2XR_007059282.1 linkn.1220A>C non_coding_transcript_exon_variant Exon 9 of 14

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
AARS2ENST00000244571.5 linkc.1196A>C p.Asn399Thr missense_variant Exon 9 of 22 1 NM_020745.4 ENSP00000244571.4 Q5JTZ9
ENSG00000272442ENST00000505802.1 linkn.313-559T>G intron_variant Intron 1 of 9 2 ENSP00000424257.1 H0Y9J4
TMEM151BENST00000438774.2 linkc.577-559T>G intron_variant Intron 2 of 2 3 ENSP00000409337.2 Q8IW70-2

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461870
Hom.:
0
Cov.:
33
AF XY:
0.00
AC XY:
0
AN XY:
727236
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
Cov.:
32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.072
BayesDel_addAF
Benign
-0.18
T
BayesDel_noAF
Benign
-0.49
CADD
Benign
1.7
DANN
Benign
0.92
DEOGEN2
Benign
0.32
T
Eigen
Benign
-1.3
Eigen_PC
Benign
-1.5
FATHMM_MKL
Benign
0.60
D
LIST_S2
Benign
0.30
T
M_CAP
Benign
0.014
T
MetaRNN
Benign
0.29
T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
1.1
L
PrimateAI
Benign
0.25
T
PROVEAN
Uncertain
-2.4
N
REVEL
Benign
0.12
Sift
Uncertain
0.0040
D
Sift4G
Uncertain
0.016
D
Polyphen
0.10
B
Vest4
0.30
MutPred
0.48
Loss of catalytic residue at N399 (P = 0.0683);
MVP
0.26
MPC
0.27
ClinPred
0.15
T
GERP RS
-7.4
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.4
Varity_R
0.13
gMVP
0.26

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-44274121; API