rs148355156

Positions:

chr16-70261144-G-A

Variant summary

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

The NM_001605.3(AARS1):c.1685C>T(p.Thr562Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0083 in 1,612,750 control chromosomes in the GnomAD database, including 92 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0057 ( 8 hom., cov: 31)

Exomes 𝑓: 0.0086 ( 84 hom. )

Consequence

AARS1
NM_001605.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13O:1

Conservation

PhyloP100: 9.99

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=0.011891067).

BP6

Variant 16-70261144-G-A is Benign according to our data. Variant chr16-70261144-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 155733.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-70261144-G-A is described in Lovd as [Benign]. Variant chr16-70261144-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00572 (870/152190) while in subpopulation NFE AF= 0.00957 (651/68008). AF 95% confidence interval is 0.00896. There are 8 homozygotes in gnomad4. There are 397 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 8 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AARS1	NM_001605.3 linkuse as main transcript	c.1685C>T	p.Thr562Ile	missense_variant	13/21	ENST00000261772.13	NP_001596.2
AARS1	XM_047433666.1 linkuse as main transcript	c.1685C>T	p.Thr562Ile	missense_variant	13/16		XP_047289622.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AARS1	ENST00000261772.13 linkuse as main transcript	c.1685C>T	p.Thr562Ile	missense_variant	13/21	1	NM_001605.3	ENSP00000261772	P1	P49588-1

Frequencies

GnomAD3 genomes

AF:

0.00573

AC:

872

AN:

152072

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00150

Gnomad AMI

AF:

0.0296

Gnomad AMR

AF:

0.00249

Gnomad ASJ

AF:

0.0156

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00217

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.00959

Gnomad OTH

AF:

0.00621

GnomAD3 exomes

AF:

0.00540

AC:

1359

AN:

251482

Hom.:

AF XY:

0.00517

AC XY:

703

AN XY:

135916

show subpopulations

Gnomad AFR exome

AF:

0.00111

Gnomad AMR exome

AF:

0.00353

Gnomad ASJ exome

AF:

0.0138

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00185

Gnomad NFE exome

AF:

0.00868

Gnomad OTH exome

AF:

0.00847

GnomAD4 exome

AF:

0.00856

AC:

12509

AN:

1460560

Hom.:

Cov.:

AF XY:

0.00840

AC XY:

6102

AN XY:

726644

show subpopulations

Gnomad4 AFR exome

AF:

0.00126

Gnomad4 AMR exome

AF:

0.00365

Gnomad4 ASJ exome

AF:

0.0147

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000812

Gnomad4 FIN exome

AF:

0.00212

Gnomad4 NFE exome

AF:

0.0102

Gnomad4 OTH exome

AF:

0.00807

GnomAD4 genome

AF:

0.00572

AC:

870

AN:

152190

Hom.:

Cov.:

AF XY:

0.00534

AC XY:

397

AN XY:

74400

show subpopulations

Gnomad4 AFR

AF:

0.00149

Gnomad4 AMR

AF:

0.00249

Gnomad4 ASJ

AF:

0.0156

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00217

Gnomad4 NFE

AF:

0.00957

Gnomad4 OTH

AF:

0.00568

Alfa

AF:

0.00890

Hom.:

Bravo

AF:

0.00564

TwinsUK

AF:

0.0108

AC:

ALSPAC

AF:

0.00778

AC:

ESP6500AA

AF:

0.00136

AC:

ESP6500EA

AF:

0.00884

AC:

ExAC

AF:

0.00530

AC:

644

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00818

EpiControl

AF:

0.00901

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:13Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:7

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 06, 2023	- -
Benign, no assertion criteria provided	literature only	Northcott Neuroscience Laboratory, ANZAC Research Institute	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	AARS1: BS1, BS2 -

Charcot-Marie-Tooth disease axonal type 2N

Benign:3Other:1

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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	Mendelics	May 28, 2019	- -
not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -
Likely benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Apr 06, 2016	- -

not specified

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital	Mar 06, 2017	BS1, BP4, BP6; This alteration has an allele frequency that is greater than expected for the associated disease, is predicted to be tolerated by multiple functional prediction tools, and was reported as a benign/likely benign alteration by a reputable source (ClinVar or other correspondence from a clinical testing laboratory). -
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

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Uncertain

0.060

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.43

Eigen

Benign

0.11

Eigen_PC

Uncertain

0.31

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.93

MetaRNN

Benign

0.012

MetaSVM

Benign

-0.85

MutationAssessor

Benign

0.67

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.68

PROVEAN

Benign

-2.2

REVEL

Uncertain

0.33

Sift

Benign

0.19

Sift4G

Benign

0.18

Polyphen

0.011

Vest4

0.74

MVP

0.84

MPC

0.21

ClinPred

0.017

GERP RS

5.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.17

gMVP

0.34

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.

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