rs35744709

Variant names:

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

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)

AARS1 links:

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 Benign/Likely_benign. ClinVar VariationId 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
AARS1	NM_001605.3 link	c.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
AARS1	ENST00000261772.13 link	c.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.:

Cov.:

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.:

AF XY:

0.0120

AC XY:

8758

AN XY:

727200

show subpopulations

African (AFR)

AF:

0.00230

AC:

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:

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:

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

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

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.:

Cov.:

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:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00145

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00762

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.0238

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0139

AC:

945

AN:

68032

Other (OTH)

AF:

0.0123

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

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

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.:

Bravo

AF:

0.00949

TwinsUK

AF:

0.0143

AC:

ALSPAC

AF:

0.0140

AC:

ESP6500AA

AF:

0.00409

AC:

ESP6500EA

AF:

0.0135

AC:

116

ExAC

AF:

0.00959

AC:

1164

Asia WGS

AF:

0.00346

AC:

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

BayesDel_noAF

Benign

-0.30

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.12

Eigen

Uncertain

0.35

Eigen_PC

Uncertain

0.37

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.73

MetaRNN

Benign

0.0089

MetaSVM

Benign

-0.72

MutationAssessor

Benign

1.6

PhyloP100

7.6

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-0.46

REVEL

Benign

0.23

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.0050

Polyphen

0.99

Vest4

0.39

MVP

0.68

MPC

0.78

ClinPred

0.028

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

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over