rs149377346

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001605.3(AARS1):c.2791G>A(p.Gly931Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00898 in 1,614,214 control chromosomes in the GnomAD database, including 115 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0071 ( 8 hom., cov: 33)

Exomes 𝑓: 0.0092 ( 107 hom. )

Consequence

AARS1
NM_001605.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 7.84

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.014511377).

BP6

Variant 16-70252837-C-T is Benign according to our data. Variant chr16-70252837-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 155735.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-70252837-C-T is described in Lovd as [Benign]. Variant chr16-70252837-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00713 (1087/152352) while in subpopulation NFE AF= 0.00978 (665/68026). AF 95% confidence interval is 0.00916. There are 8 homozygotes in gnomad4. There are 498 alleles in male gnomad4 subpopulation. This position pass quality control queck.

BS2

High Homozygotes in GnomAd at 8 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AARS1	NM_001605.3 linkuse as main transcript	c.2791G>A	p.Gly931Ser	missense_variant	21/21	ENST00000261772.13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AARS1	ENST00000261772.13 linkuse as main transcript	c.2791G>A	p.Gly931Ser	missense_variant	21/21	1	NM_001605.3	P1	P49588-1

Frequencies

GnomAD3 genomes

AF:

0.00713

AC:

1086

AN:

152234

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00193

Gnomad AMI

AF:

0.0296

Gnomad AMR

AF:

0.00923

Gnomad ASJ

AF:

0.0274

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00351

Gnomad FIN

AF:

0.00188

Gnomad MID

AF:

0.0348

Gnomad NFE

AF:

0.00977

Gnomad OTH

AF:

0.0139

GnomAD3 exomes

AF:

0.00776

AC:

1952

AN:

251438

Hom.:

AF XY:

0.00812

AC XY:

1104

AN XY:

135894

show subpopulations

Gnomad AFR exome

AF:

0.00117

Gnomad AMR exome

AF:

0.00596

Gnomad ASJ exome

AF:

0.0346

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00255

Gnomad FIN exome

AF:

0.00226

Gnomad NFE exome

AF:

0.0104

Gnomad OTH exome

AF:

0.0114

GnomAD4 exome

AF:

0.00917

AC:

13401

AN:

1461862

Hom.:

107

Cov.:

AF XY:

0.00919

AC XY:

6680

AN XY:

727230

show subpopulations

Gnomad4 AFR exome

AF:

0.00170

Gnomad4 AMR exome

AF:

0.00637

Gnomad4 ASJ exome

AF:

0.0359

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.00247

Gnomad4 FIN exome

AF:

0.00217

Gnomad4 NFE exome

AF:

0.00990

Gnomad4 OTH exome

AF:

0.0103

GnomAD4 genome

AF:

0.00713

AC:

1087

AN:

152352

Hom.:

Cov.:

AF XY:

0.00668

AC XY:

498

AN XY:

74506

show subpopulations

Gnomad4 AFR

AF:

0.00192

Gnomad4 AMR

AF:

0.00922

Gnomad4 ASJ

AF:

0.0274

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00372

Gnomad4 FIN

AF:

0.00188

Gnomad4 NFE

AF:

0.00978

Gnomad4 OTH

AF:

0.0137

Alfa

AF:

0.0110

Hom.:

Bravo

AF:

0.00822

TwinsUK

AF:

0.0116

AC:

ALSPAC

AF:

0.0104

AC:

ESP6500AA

AF:

0.00182

AC:

ESP6500EA

AF:

0.0106

AC:

ExAC

AF:

0.00714

AC:

867

Asia WGS

AF:

0.00231

AC:

AN:

3478

EpiCase

AF:

0.0123

EpiControl

AF:

0.0130

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Benign, no assertion criteria provided	literature only	Northcott Neuroscience Laboratory, ANZAC Research Institute	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	AARS1: BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 12, 2023	- -

Charcot-Marie-Tooth disease axonal type 2N

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -
Likely benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 09, 2014	- -

not specified

Benign:1

Benign, no assertion criteria provided

clinical testing

Clinical Genetics, Academic Medical Center

- -

Charcot-Marie-Tooth disease type 2

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.73

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.11

Cadd

Pathogenic

Dann

Uncertain

1.0

DEOGEN2

Uncertain

0.69

Eigen

Pathogenic

0.80

Eigen_PC

Pathogenic

0.75

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.96

MetaRNN

Benign

0.015

MetaSVM

Uncertain

0.55

MutationAssessor

Pathogenic

3.5

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.78

PROVEAN

Pathogenic

-5.0

REVEL

Pathogenic

0.73

Sift

Benign

0.21

Sift4G

Benign

0.10

Polyphen

0.99

Vest4

0.68

MVP

0.91

MPC

0.67

ClinPred

0.023

GERP RS

5.4

Varity_R

0.57

gMVP

0.83

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

LitVar

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

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over