rs11537667

chr16-70269756-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001605.3(AARS1):c.824G>A(p.Gly275Asp) variant causes a missense change. The variant allele was found at a frequency of 0.013 in 1,614,020 control chromosomes in the GnomAD database, including 2,437 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G275S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.071 (1283 hom., cov: 31)
  • Exomes 𝑓: 0.0070 (1154 hom.)
• Consequence: AARS1 NM_001605.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 5.04

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0017437637).
• BP6: Variant 16-70269756-C-T is Benign according to our data. Variant chr16-70269756-C-T is described in ClinVar as [Benign]. Clinvar id is 320348.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-70269756-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.242 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AARS1	NM_001605.3	c.824G>A	p.Gly275Asp	missense_variant	7/21	ENST00000261772.13
AARS1	XM_047433666.1	c.824G>A	p.Gly275Asp	missense_variant	7/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AARS1	ENST00000261772.13	c.824G>A	p.Gly275Asp	missense_variant	7/21	1	NM_001605.3	P1

Frequencies

GnomAD3 genomes AF: 0.0710 AC: 10792 AN: 152040 Hom.: 1282 Cov.: 31

Gnomad AFR AF: 0.246

Gnomad AMI AF: 0.0439

Gnomad AMR AF: 0.0271

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000618

Gnomad OTH AF: 0.0497

GnomAD3 exomes AF: 0.0178 AC: 4470 AN: 251436 Hom.: 543 AF XY: 0.0133 AC XY: 1809 AN XY: 135896

Gnomad AFR exome AF: 0.247

Gnomad AMR exome AF: 0.0102

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000359

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000396

Gnomad OTH exome AF: 0.00668

GnomAD4 exome AF: 0.00696 AC: 10180 AN: 1461862 Hom.: 1154 Cov.: 35 AF XY: 0.00598 AC XY: 4350 AN XY: 727228

Gnomad4 AFR exome AF: 0.250

Gnomad4 AMR exome AF: 0.0117

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000441

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000263

Gnomad4 OTH exome AF: 0.0151

GnomAD4 genome AF: 0.0710 AC: 10797 AN: 152158 Hom.: 1283 Cov.: 31 AF XY: 0.0690 AC XY: 5131 AN XY: 74404

Gnomad4 AFR AF: 0.246

Gnomad4 AMR AF: 0.0271

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.000618

Gnomad4 OTH AF: 0.0492

Alfa AF: 0.0124 Hom.: 391

Bravo AF: 0.0790

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.229 AC: 1005

ESP6500EA AF: 0.000814 AC: 7

ExAC AF: 0.0219 AC: 2660

Asia WGS AF: 0.0120 AC: 42 AN: 3478

EpiCase AF: 0.000600

EpiControl AF: 0.000533

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 30, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Charcot-Marie-Tooth disease axonal type 2N Benign:2

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. -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

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	Benign	0.15
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.24
Cadd	Pathogenic	28
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.82	D
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.97	D
MetaRNN	Benign	0.0017	T
MetaSVM	Benign	-1.2	T
MutationAssessor	Uncertain	2.7	M
MutationTaster	Benign	2.5e-19	P
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-5.0	D
REVEL	Uncertain	0.38
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.016	D
Polyphen		0.99	D
Vest4		0.17
MPC		0.77
ClinPred		0.024	T
GERP RS		5.7
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		2.8
Varity_R		0.91
gMVP		0.78

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

Other links and lift over

dbSNP: rs11537667; hg19: chr16-70303659;