rs138081804

Positions:

• chr16-70255829-G-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4 BP6 BS1 BS2

The NM_001605.3(AARS1):​c.2185C>T​(p.Arg729Trp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00125 in 1,613,164 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R729Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00070 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0013 (3 hom.)
• Consequence: AARS1 NM_001605.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:7
• Conservation: PhyloP100: 7.83

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.34738052).
• BP6: Variant 16-70255829-G-A is Benign according to our data. Variant chr16-70255829-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 155734.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=5, Benign=1, Likely_benign=2}. Variant chr16-70255829-G-A is described in Lovd as [Likely_benign]. Variant chr16-70255829-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000702 (107/152314) while in subpopulation NFE AF= 0.00129 (88/68030). AF 95% confidence interval is 0.00107. There are 0 homozygotes in gnomad4. There are 48 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AARS1	NM_001605.3	c.2185C>T	p.Arg729Trp	missense_variant	16/21	ENST00000261772.13
AARS1	XM_047433666.1	c.2000C>T	p.Ala667Val	missense_variant	15/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AARS1	ENST00000261772.13	c.2185C>T	p.Arg729Trp	missense_variant	16/21	1	NM_001605.3	P1

Frequencies

GnomAD3 genomes AF: 0.000710 AC: 108 AN: 152196 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

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: 0.00131

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.000647 AC: 161 AN: 249026 Hom.: 1 AF XY: 0.000601 AC XY: 81 AN XY: 134678

Gnomad AFR exome AF: 0.000311

Gnomad AMR exome AF: 0.000524

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: 0.00119

Gnomad OTH exome AF: 0.000657

GnomAD4 exome AF: 0.00130 AC: 1905 AN: 1460850 Hom.: 3 Cov.: 31 AF XY: 0.00120 AC XY: 871 AN XY: 726666

Gnomad4 AFR exome AF: 0.000269

Gnomad4 AMR exome AF: 0.000426

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000233

Gnomad4 FIN exome AF: 0.0000750

Gnomad4 NFE exome AF: 0.00165

Gnomad4 OTH exome AF: 0.000679

GnomAD4 genome AF: 0.000702 AC: 107 AN: 152314 Hom.: 0 Cov.: 31 AF XY: 0.000645 AC XY: 48 AN XY: 74472

Gnomad4 AFR AF: 0.000313

Gnomad4 AMR AF: 0.000261

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00129

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.00110 Hom.: 0

Bravo AF: 0.000684

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.00208 AC: 8

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.000428 AC: 52

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3 Benign:5

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Mar 28, 2017	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Oct 17, 2023	Reported in individuals with Charcot-Marie-Tooth disease; however it was also identified in 2/1090 normal control chromosomes (PMID: 22009580); Reported as a variant of uncertain significance in an individual with CMT2; the patient was also found to have a variant in another gene and it was unclear if either variant was causative for the patient's phenotype (PMID: 26752306); Reported in an individual with axonal neuropathy; the R729W variant does not segregate with disease in the family as it was observed in both affected and unaffected family members and was absent in affected family members, and the patient was also found to have a variant in another gene that appears to segregate with disease in the family (PMID: 30642740); 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: 32376792, 25817015, Elshiekh2020[article], 22009580, 26752306, 30642740) -
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	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 10, 2020	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	literature only	Northcott Neuroscience Laboratory, ANZAC Research Institute	-	- -

Charcot-Marie-Tooth disease Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Molecular Genetics Laboratory, London Health Sciences Centre

-

- -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 31, 2023

Unlikely to be causative of AARS-related Charcot-Marie-Tooth disease, type 2 (AD) Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Charcot-Marie-Tooth disease type 2 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Charcot-Marie-Tooth disease axonal type 2N Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 28, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.17
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.84	D
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.35	T
MetaSVM	Uncertain	-0.24	T
MutationAssessor	Uncertain	2.9	M
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.30	T
PROVEAN	Uncertain	-3.5	D
REVEL	Uncertain	0.32
Sift	Uncertain	0.0080	D
Sift4G	Uncertain	0.017	D
Polyphen		0.96	D
Vest4		0.48
MVP		0.88
MPC		0.52
ClinPred		0.11	T
GERP RS		5.0
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.1
Varity_R		0.19
gMVP		0.50

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: rs138081804; hg19: chr16-70289732;