rs2270004

chr1-54758458-T-C

Variant summary

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

The NM_152268.4(PARS2):c.704A>G(p.Asn235Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.155 in 1,613,830 control chromosomes in the GnomAD database, including 19,963 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.15 (1825 hom., cov: 32)
  • Exomes 𝑓: 0.16 (18138 hom.)
• Consequence: PARS2 NM_152268.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.209

Genes affected

PARS2 (HGNC:30563): (prolyl-tRNA synthetase 2, mitochondrial) This gene encodes a putative member of the class II family of aminoacyl-tRNA synthetases. These enzymes play a critical role in protein biosynthesis by charging tRNAs with their cognate amino acids. This protein is encoded by the nuclear genome but is likely to be imported to the mitochondrion where it is thought to catalyze the ligation of proline to tRNA molecules. Mutations have been found in this gene in some patients with Alpers syndrome. [provided by RefSeq, Mar 2015]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002560705).
• BP6: Variant 1-54758458-T-C is Benign according to our data. Variant chr1-54758458-T-C is described in ClinVar as [Benign]. Clinvar id is 380003.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.174 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PARS2	NM_152268.4	c.704A>G	p.Asn235Ser	missense_variant	2/2	ENST00000371279.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PARS2	ENST00000371279.4	c.704A>G	p.Asn235Ser	missense_variant	2/2	1	NM_152268.4	P1

Frequencies

GnomAD3 genomes AF: 0.153 AC: 23224 AN: 151930 Hom.: 1823 Cov.: 32

Gnomad AFR AF: 0.141

Gnomad AMI AF: 0.116

Gnomad AMR AF: 0.142

Gnomad ASJ AF: 0.109

Gnomad EAS AF: 0.171

Gnomad SAS AF: 0.184

Gnomad FIN AF: 0.213

Gnomad MID AF: 0.222

Gnomad NFE AF: 0.151

Gnomad OTH AF: 0.164

GnomAD3 exomes AF: 0.156 AC: 39201 AN: 251262 Hom.: 3284 AF XY: 0.160 AC XY: 21760 AN XY: 135808

Gnomad AFR exome AF: 0.145

Gnomad AMR exome AF: 0.0996

Gnomad ASJ exome AF: 0.107

Gnomad EAS exome AF: 0.163

Gnomad SAS exome AF: 0.190

Gnomad FIN exome AF: 0.206

Gnomad NFE exome AF: 0.159

Gnomad OTH exome AF: 0.160

GnomAD4 exome AF: 0.155 AC: 227026 AN: 1461782 Hom.: 18138 Cov.: 34 AF XY: 0.157 AC XY: 113929 AN XY: 727188

Gnomad4 AFR exome AF: 0.148

Gnomad4 AMR exome AF: 0.105

Gnomad4 ASJ exome AF: 0.111

Gnomad4 EAS exome AF: 0.189

Gnomad4 SAS exome AF: 0.191

Gnomad4 FIN exome AF: 0.200

Gnomad4 NFE exome AF: 0.152

Gnomad4 OTH exome AF: 0.156

GnomAD4 genome AF: 0.153 AC: 23237 AN: 152048 Hom.: 1825 Cov.: 32 AF XY: 0.157 AC XY: 11657 AN XY: 74334

Gnomad4 AFR AF: 0.141

Gnomad4 AMR AF: 0.142

Gnomad4 ASJ AF: 0.109

Gnomad4 EAS AF: 0.172

Gnomad4 SAS AF: 0.184

Gnomad4 FIN AF: 0.213

Gnomad4 NFE AF: 0.151

Gnomad4 OTH AF: 0.163

Alfa AF: 0.150 Hom.: 2978

Bravo AF: 0.147

TwinsUK AF: 0.155 AC: 573

ALSPAC AF: 0.155 AC: 597

ESP6500AA AF: 0.141 AC: 622

ESP6500EA AF: 0.144 AC: 1241

ExAC AF: 0.161 AC: 19514

Asia WGS AF: 0.167 AC: 580 AN: 3478

EpiCase AF: 0.157

EpiControl AF: 0.159

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jan 18, 2016

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.055
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.64
Cadd	Benign	0.074
Dann	Benign	0.31
DEOGEN2	Benign	0.10	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.13	N
LIST_S2	Uncertain	0.86	D
MetaRNN	Benign	0.0026	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.59	N
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.20	T
PROVEAN	Benign	-0.76	N
REVEL	Benign	0.054
Sift	Benign	0.53	T
Sift4G	Benign	0.60	T
Polyphen		0.0	B
Vest4		0.029
MPC		0.15
ClinPred		0.0014	T
GERP RS		-2.1
Varity_R		0.025
gMVP		0.11

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: rs2270004; hg19: chr1-55224131; COSMIC: COSV64883505;