chr16-70255763-T-C

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PP3_StrongPP5

The NM_001605.3(AARS1):c.2251A>G(p.Arg751Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000135 in 1,614,142 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00014 ( 0 hom. )

Consequence

AARS1
NM_001605.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5U:4

Conservation

PhyloP100: 3.98

Publications

13 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: Uncertain_significance. The variant received 5 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.983

PP5

Variant 16-70255763-T-C is Pathogenic according to our data. Variant chr16-70255763-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 190103.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AARS1	NM_001605.3 link	c.2251A>G	p.Arg751Gly	missense_variant	Exon 16 of 21	ENST00000261772.13	NP_001596.2	P49588-1
AARS1	XM_047433666.1 link	c.2066A>G	p.Glu689Gly	missense_variant	Exon 15 of 16		XP_047289622.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AARS1	ENST00000261772.13 link	c.2251A>G	p.Arg751Gly	missense_variant	Exon 16 of 21	1	NM_001605.3	ENSP00000261772.8		P49588-1

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000477

AC:

AN:

251408

AF XY:

0.0000442

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000967

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000144

AC:

210

AN:

1461866

Hom.:

Cov.:

AF XY:

0.000136

AC XY:

AN XY:

727230

show subpopulations

African (AFR)

AF:

0.0000597

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000183

AC:

203

AN:

1111996

Other (OTH)

AF:

0.0000828

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

GnomAD4 genome

AF:

0.0000525

AC:

AN:

152276

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74450

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41550

American (AMR)

AF:

0.00

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000103

AC:

AN:

68024

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.0000710

Hom.:

Bravo

AF:

0.0000680

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000494

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5Uncertain:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:1Uncertain:1

Aug 08, 2025

GeneDx

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 33317386, 26670257, 25817015, 27159321, 31775912, 33294374, 34446925, 32376792, 34490615, 29653220, 36991000, 38979321, 40491354, 39487674) -

Feb 15, 2021

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

BS1, PS3_Supporting, PP3, PM1 -

Developmental and epileptic encephalopathy, 29

Pathogenic:1

Apr 02, 2015

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Charcot-Marie-Tooth disease type 2

Pathogenic:1

Sep 21, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 751 of the AARS protein (p.Arg751Gly). This variant is present in population databases (rs143370729, gnomAD 0.009%). This missense change has been observed in individuals with autosomal recessive epileptic encephalopathy (PMID: 25817015, 33294374). It has also been observed to segregate with disease in related individuals. This variant has been reported in individual(s) with autosomal dominant Charcot-Marie-Tooth disease (PMID: 29653220); however, the role of the variant in this condition is currently unclear. ClinVar contains an entry for this variant (Variation ID: 190103). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt AARS protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects AARS function (PMID: 25817015). For these reasons, this variant has been classified as Pathogenic. -

AARS-related disorder

Pathogenic:1

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant has been previously reported in heterozygous, compound heterozygous or homozygous state in patients with AARS-related disorders (PMID: 25817015, 33294374, 29653220). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.005% (13/282822) and thus is presumed to be rare. This variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Experimental studies have shown that this variant reduces the normal function of the AARS protein (PMID: 25817015). Based on the available evidence, the c.2251A>G (p.Arg751Gly) variant is classified as Likely Pathogenic. -

AARS1-related disorder

Pathogenic:1

Aug 05, 2024

PreventionGenetics, part of Exact Sciences

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

The AARS1 c.2251A>G variant is predicted to result in the amino acid substitution p.Arg751Gly. This variant has been reported in the compound heterozygous and homozygous state in individuals with early infantile epileptic encephalopathy (Simons et al. 2015. PubMed ID: 25817015). This variant has been reported in in the compound heterozygous in an individual with acute liver failure (Marten et al. 2020. PubMed ID: 33294374). This variant has also been reported in an individual with autosomal dominant Charcot-Marie-Tooth disease (Table S5, Vaeth et al. 2018. PubMed ID: 29653220). In addition, functional studies indicate this variant impairs the aminoacylation activity of the AARS protein (Simons et al. 2015. PubMed ID: 25817015; Marten et al. 2020. PubMed ID: 33294374). This variant is reported in 0.0093% of alleles in individuals of European (Non-Finnish) descent in gnomAD and has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from uncertain to pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/190103/). This variant is interpreted as likely pathogenic. -

Charcot-Marie-Tooth disease

Uncertain:1

Molecular Genetics Laboratory, London Health Sciences Centre

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Uncertain:1

May 19, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.R751G variant (also known as c.2251A>G), located in coding exon 15 of the AARS gene, results from an A to G substitution at nucleotide position 2251. The arginine at codon 751 is replaced by glycine, an amino acid with dissimilar properties. This alteration was detected in an individual among a cohort of Charcot-Marie-Tooth disease patients (Vaeth S et al. Eur J Med Genet, 2019 Jan;62:1-8). Furthermore, functional studies showed reduced aminoacylation activity in vitro (Simons C et al. Am J Hum Genet, 2015 Apr;96:675-81). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. However, based on data from gnomAD, the frequency for this variant is above the maximum credible frequency for a disease-causing variant in this gene based on internally established thresholds (Karczewski et al. Nature. 2020 May;581(7809):434-443; Whiffin et al. Genet Med. 2017 10;19:1151-1158). Since supporting evidence is conflicting at this time, the clinical significance of this alteration remains unclear. -

Charcot-Marie-Tooth disease axonal type 2N

Uncertain:1

Apr 20, 2017

Inherited Neuropathy Consortium Ii, University Of Miami

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.27

BayesDel_noAF

Pathogenic

0.35

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.94

Eigen

Pathogenic

0.80

Eigen_PC

Pathogenic

0.67

FATHMM_MKL

Uncertain

0.92

LIST_S2

Pathogenic

0.99

M_CAP

Pathogenic

0.72

MetaRNN

Pathogenic

0.98

MetaSVM

Uncertain

0.69

MutationAssessor

Pathogenic

4.7

PhyloP100

4.0

PrimateAI

Uncertain

0.72

PROVEAN

Pathogenic

-6.6

REVEL

Pathogenic

0.96

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0020

Polyphen

1.0

Vest4

0.98

MVP

0.93

MPC

0.21

ClinPred

0.92

GERP RS

4.8

Varity_R

0.98

gMVP

0.94

Mutation Taster

=13/87

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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