rs770980206

Positions:

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6_Very_StrongBP7

The NM_001605.3(AARS1):c.2217C>T(p.Ile739=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000225 in 1,614,012 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00022 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00023 ( 0 hom. )

Consequence

AARS1
NM_001605.3 synonymous

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 0.0730

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 -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.5).

BP6

Variant 16-70255797-G-A is Benign according to our data. Variant chr16-70255797-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 320332.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-70255797-G-A is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=0.073 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AARS1	NM_001605.3 linkuse as main transcript	c.2217C>T	p.Ile739=	synonymous_variant	16/21	ENST00000261772.13	NP_001596.2
AARS1	XM_047433666.1 linkuse as main transcript	c.2032C>T	p.Arg678Cys	missense_variant	15/16		XP_047289622.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AARS1	ENST00000261772.13 linkuse as main transcript	c.2217C>T	p.Ile739=	synonymous_variant	16/21	1	NM_001605.3	ENSP00000261772	P1	P49588-1

Frequencies

GnomAD3 genomes

AF:

0.000217

AC:

AN:

152180

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.000426

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000235

AC:

AN:

251256

Hom.:

AF XY:

0.000169

AC XY:

AN XY:

135830

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.000376

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000334

Gnomad OTH exome

AF:

0.00114

GnomAD4 exome

AF:

0.000226

AC:

330

AN:

1461832

Hom.:

Cov.:

AF XY:

0.000216

AC XY:

157

AN XY:

727216

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.000380

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000272

Gnomad4 OTH exome

AF:

0.000149

GnomAD4 genome

AF:

0.000217

AC:

AN:

152180

Hom.:

Cov.:

AF XY:

0.000108

AC XY:

AN XY:

74342

show subpopulations

Gnomad4 AFR

AF:

0.0000724

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000426

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000278

Hom.:

Bravo

AF:

0.000212

EpiCase

AF:

0.000382

EpiControl

AF:

0.000119

ClinVar

Significance: Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 03, 2018	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	AARS1: BP4, BP7 -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 11, 2019

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Charcot-Marie-Tooth disease type 2

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 24, 2024

- -

Charcot-Marie-Tooth disease axonal type 2N

Benign:1

Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.50

CADD

Benign

4.8

DANN

Benign

0.85

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