16-70252758-G-C

Position:

• chr16-70252758-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.

The NM_001605.3(AARS1):​c.2870C>G​(p.Ser957Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000123 in 1,461,840 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: AARS1 NM_001605.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 4.49

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 Uncertain_significance. Variant got 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AARS1	NM_001605.3	c.2870C>G	p.Ser957Cys	missense_variant	21/21	ENST00000261772.13	NP_001596.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AARS1	ENST00000261772.13	c.2870C>G	p.Ser957Cys	missense_variant	21/21	1	NM_001605.3	ENSP00000261772	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251400 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135886

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000123 AC: 18 AN: 1461840 Hom.: 0 Cov.: 31 AF XY: 0.0000165 AC XY: 12 AN XY: 727228

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.0000162

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 29, 2020

The p.S957C variant (also known as c.2870C>G), located in coding exon 20 of the AARS gene, results from a C to G substitution at nucleotide position 2870. The serine at codon 957 is replaced by cysteine, an amino acid with dissimilar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Charcot-Marie-Tooth disease type 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 20, 2023

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt AARS protein function. ClinVar contains an entry for this variant (Variation ID: 565349). This variant has not been reported in the literature in individuals affected with AARS-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.0009%). This sequence change replaces serine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 957 of the AARS protein (p.Ser957Cys). -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Jun 07, 2017

The p.Ser957Cys variant has not been reported in the medical literature, is not listed in gene-specific variant databases, nor has it been previously identified in our laboratory. It is listed in the Genome Aggregation Database (gnomAD) browser with an overall frequency of 0.0004% (identified in 1 out of 246,202 chromosomes). The serine at codon 957 is moderately conserved considering 15 species (Alamut software v2.9), and computational analyses return mixed results regarding the effect of this variant on AARS protein structure/function (SIFT: damaging, PolyPhen2: possibly damaging, and Mutation Taster: polymorphism). Thus, based on the available information, the clinical significance of the p.Ser957Cys variant cannot be determined with certainty. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.033	T
BayesDel_noAF	Benign	-0.29
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.77	D
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.027	D
MetaRNN	Uncertain	0.46	T
MetaSVM	Benign	-0.42	T
MutationAssessor	Benign	1.5	L
MutationTaster	Benign	0.71	N
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-2.6	D
REVEL	Benign	0.21
Sift	Uncertain	0.0090	D
Sift4G	Uncertain	0.018	D
Polyphen		0.85	P
Vest4		0.24
MutPred		0.50		Loss of disorder (P = 0.105);
MVP		0.86
MPC		0.44
ClinPred		0.90	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.9
Varity_R		0.32
gMVP		0.32

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: rs146540551; hg19: chr16-70286661;