16-70252748-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001605.3(AARS1):ā€‹c.2880G>Cā€‹(p.Gln960His) 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 1,461,804 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. Variant has been reported in ClinVar as Uncertain significance (ā˜…ā˜…). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q960P) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)
Exomes š‘“: 6.8e-7 ( 0 hom. )

Consequence

AARS1
NM_001605.3 missense

Scores

3
16

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 0.137
Variant links:
Genes affected
AARS1 (HGNC:20): (alanyl-tRNA synthetase 1) The human alanyl-tRNA synthetase (AARS) belongs to a family of tRNA synthases, of the class II enzymes. Class II tRNA synthases evolved early in evolution and are highly conserved. This is reflected by the fact that 498 of the 968-residue polypeptide human AARS shares 41% identity witht the E.coli protein. tRNA synthases are the enzymes that interpret the RNA code and attach specific aminoacids to the tRNAs that contain the cognate trinucleotide anticodons. They consist of a catalytic domain which interacts with the amino acid acceptor-T psi C helix of the tRNA, and a second domain which interacts with the rest of the tRNA structure. [provided by RefSeq, Jul 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.17393947).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
AARS1NM_001605.3 linkuse as main transcriptc.2880G>C p.Gln960His missense_variant 21/21 ENST00000261772.13

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
AARS1ENST00000261772.13 linkuse as main transcriptc.2880G>C p.Gln960His missense_variant 21/211 NM_001605.3 P1P49588-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD3 exomes
AF:
0.00000398
AC:
1
AN:
251362
Hom.:
0
AF XY:
0.00000736
AC XY:
1
AN XY:
135862
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000289
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461804
Hom.:
0
Cov.:
31
AF XY:
0.00000138
AC XY:
1
AN XY:
727218
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000224
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:
0.00
GnomAD4 genome
Cov.:
33
ExAC
AF:
0.00000824
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsJun 22, 2021The c.2880G>C (p.Q960H) alteration is located in exon 21 (coding exon 20) of the AARS gene. This alteration results from a G to C substitution at nucleotide position 2880, causing the glutamine (Q) at amino acid position 960 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
Charcot-Marie-Tooth disease type 2 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingInvitaeSep 03, 2023This sequence change replaces glutamine, which is neutral and polar, with histidine, which is basic and polar, at codon 960 of the AARS protein (p.Gln960His). This variant is present in population databases (rs779509100, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with AARS-related conditions. ClinVar contains an entry for this variant (Variation ID: 2234316). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt AARS protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.15
BayesDel_addAF
Benign
-0.19
T
BayesDel_noAF
Benign
-0.43
CADD
Benign
15
DANN
Uncertain
0.98
DEOGEN2
Benign
0.22
T
Eigen
Benign
-0.33
Eigen_PC
Benign
-0.18
FATHMM_MKL
Uncertain
0.87
D
LIST_S2
Uncertain
0.86
D
M_CAP
Benign
0.014
T
MetaRNN
Benign
0.17
T
MetaSVM
Benign
-0.94
T
MutationAssessor
Benign
1.6
L
MutationTaster
Benign
0.93
D
PrimateAI
Benign
0.39
T
PROVEAN
Benign
-1.4
N
REVEL
Benign
0.066
Sift
Benign
0.040
D
Sift4G
Benign
0.14
T
Polyphen
0.0010
B
Vest4
0.10
MutPred
0.28
Loss of loop (P = 0.1242);
MVP
0.74
MPC
0.15
ClinPred
0.12
T
GERP RS
2.3
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.9
Varity_R
0.14
gMVP
0.27

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs779509100; hg19: chr16-70286651; API