rs35744709

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001605.3(AARS1):​c.2900A>T​(p.Lys967Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.012 in 1,614,088 control chromosomes in the GnomAD database, including 157 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K967N) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0094 ( 10 hom., cov: 33)
Exomes 𝑓: 0.012 ( 147 hom. )

Consequence

AARS1
NM_001605.3 missense

Scores

1
6
11

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 7.57

Publications

11 publications found
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]
AARS1 Gene-Disease associations (from GenCC):
  • Charcot-Marie-Tooth disease axonal type 2N
    Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Orphanet
  • undetermined early-onset epileptic encephalopathy
    Inheritance: AR, AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Illumina, Orphanet
  • developmental and epileptic encephalopathy, 29
    Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
  • trichothiodystrophy 8, nonphotosensitive
    Inheritance: AR, Unknown Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.0089383125).
BP6
Variant 16-70252728-T-A is Benign according to our data. Variant chr16-70252728-T-A is described in ClinVar as [Likely_benign]. Clinvar id is 220723.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS1
Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00941 (1433/152320) while in subpopulation NFE AF = 0.0139 (945/68032). AF 95% confidence interval is 0.0132. There are 10 homozygotes in GnomAd4. There are 700 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
BS2
High Homozygotes in GnomAd4 at 10 AD,AR,Unknown gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
AARS1NM_001605.3 linkc.2900A>T p.Lys967Met missense_variant Exon 21 of 21 ENST00000261772.13 NP_001596.2 P49588-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
AARS1ENST00000261772.13 linkc.2900A>T p.Lys967Met missense_variant Exon 21 of 21 1 NM_001605.3 ENSP00000261772.8 P49588-1

Frequencies

GnomAD3 genomes
AF:
0.00942
AC:
1433
AN:
152202
Hom.:
10
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00241
Gnomad AMI
AF:
0.00110
Gnomad AMR
AF:
0.0111
Gnomad ASJ
AF:
0.0280
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00166
Gnomad FIN
AF:
0.00762
Gnomad MID
AF:
0.0222
Gnomad NFE
AF:
0.0139
Gnomad OTH
AF:
0.0124
GnomAD2 exomes
AF:
0.00992
AC:
2493
AN:
251344
AF XY:
0.00994
show subpopulations
Gnomad AFR exome
AF:
0.00302
Gnomad AMR exome
AF:
0.00798
Gnomad ASJ exome
AF:
0.0255
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00853
Gnomad NFE exome
AF:
0.0140
Gnomad OTH exome
AF:
0.0139
GnomAD4 exome
AF:
0.0123
AC:
17971
AN:
1461768
Hom.:
147
Cov.:
31
AF XY:
0.0120
AC XY:
8758
AN XY:
727200
show subpopulations
African (AFR)
AF:
0.00230
AC:
77
AN:
33480
American (AMR)
AF:
0.00847
AC:
379
AN:
44724
Ashkenazi Jewish (ASJ)
AF:
0.0290
AC:
758
AN:
26136
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39698
South Asian (SAS)
AF:
0.00182
AC:
157
AN:
86250
European-Finnish (FIN)
AF:
0.00806
AC:
430
AN:
53324
Middle Eastern (MID)
AF:
0.0102
AC:
59
AN:
5764
European-Non Finnish (NFE)
AF:
0.0139
AC:
15404
AN:
1112000
Other (OTH)
AF:
0.0117
AC:
707
AN:
60392
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.481
Heterozygous variant carriers
0
997
1993
2990
3986
4983
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
556
1112
1668
2224
2780
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.00941
AC:
1433
AN:
152320
Hom.:
10
Cov.:
33
AF XY:
0.00940
AC XY:
700
AN XY:
74474
show subpopulations
African (AFR)
AF:
0.00241
AC:
100
AN:
41566
American (AMR)
AF:
0.0110
AC:
169
AN:
15300
Ashkenazi Jewish (ASJ)
AF:
0.0280
AC:
97
AN:
3470
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5182
South Asian (SAS)
AF:
0.00145
AC:
7
AN:
4828
European-Finnish (FIN)
AF:
0.00762
AC:
81
AN:
10626
Middle Eastern (MID)
AF:
0.0238
AC:
7
AN:
294
European-Non Finnish (NFE)
AF:
0.0139
AC:
945
AN:
68032
Other (OTH)
AF:
0.0123
AC:
26
AN:
2112
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.503
Heterozygous variant carriers
0
81
162
242
323
404
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Genome Hom
Variant carriers
0
20
40
60
80
100
<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:
0.0144
Hom.:
8
Bravo
AF:
0.00949
TwinsUK
AF:
0.0143
AC:
53
ALSPAC
AF:
0.0140
AC:
54
ESP6500AA
AF:
0.00409
AC:
18
ESP6500EA
AF:
0.0135
AC:
116
ExAC
AF:
0.00959
AC:
1164
Asia WGS
AF:
0.00346
AC:
13
AN:
3478
EpiCase
AF:
0.0150
EpiControl
AF:
0.0142

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:9
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:4
May 01, 2025
CeGaT Center for Human Genetics Tuebingen
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

AARS1: BS1, BS2 -

-
Breakthrough Genomics, Breakthrough Genomics
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:not provided

- -

Mar 03, 2015
GeneDx
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Sep 03, 2024
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Charcot-Marie-Tooth disease axonal type 2N Benign:2
Jan 13, 2018
Illumina Laboratory Services, Illumina
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Oct 09, 2014
Genome Diagnostics Laboratory, University Medical Center Utrecht
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

not specified Benign:1
-
Clinical Genetics, Academic Medical Center
Significance:Benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

Charcot-Marie-Tooth disease type 2 Benign:1
Feb 04, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Charcot-Marie-Tooth disease axonal type 2N;C4225361:Developmental and epileptic encephalopathy, 29;C5562044:Leukoencephalopathy, hereditary diffuse, with spheroids 2;C5562057:Trichothiodystrophy 8, nonphotosensitive Benign:1
Aug 13, 2021
Fulgent Genetics, Fulgent Genetics
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.18
BayesDel_addAF
Benign
-0.38
T
BayesDel_noAF
Benign
-0.30
CADD
Benign
22
DANN
Uncertain
1.0
DEOGEN2
Benign
0.12
T
Eigen
Uncertain
0.35
Eigen_PC
Uncertain
0.37
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Benign
0.73
T
MetaRNN
Benign
0.0089
T
MetaSVM
Benign
-0.72
T
MutationAssessor
Benign
1.6
L
PhyloP100
7.6
PrimateAI
Uncertain
0.55
T
PROVEAN
Benign
-0.46
N
REVEL
Benign
0.23
Sift
Uncertain
0.0020
D
Sift4G
Uncertain
0.0050
D
Polyphen
0.99
D
Vest4
0.39
MVP
0.68
MPC
0.78
ClinPred
0.028
T
GERP RS
4.3
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.8
Varity_R
0.13
gMVP
0.51
Mutation Taster
=93/7
polymorphism

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

Other links and lift over

dbSNP: rs35744709; hg19: chr16-70286631; COSMIC: COSV99028685; COSMIC: COSV99028685; API