rs11539445

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001040436.3(YARS2):c.572G>T(p.Gly191Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.135 in 1,613,962 control chromosomes in the GnomAD database, including 15,104 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.14 ( 1556 hom., cov: 32)

Exomes 𝑓: 0.13 ( 13548 hom. )

Consequence

YARS2
NM_001040436.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 3.46

Variant links:

Genes affected

YARS2 (HGNC:24249): (tyrosyl-tRNA synthetase 2) This gene encodes a mitochondrial protein that catalyzes the attachment of tyrosine to tRNA(Tyr). Mutations in this gene are associated with myopathy with lactic acidosis and sideroblastic anemia type 2 (MLASA2). [provided by RefSeq, Jan 2011]

YARS2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0023421645).

BP6

Variant 12-32755303-C-A is Benign according to our data. Variant chr12-32755303-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 308460.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-32755303-C-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.166 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
YARS2	NM_001040436.3 linkuse as main transcript	c.572G>T	p.Gly191Val	missense_variant	1/5	ENST00000324868.13	NP_001035526.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
YARS2	ENST00000324868.13 linkuse as main transcript	c.572G>T	p.Gly191Val	missense_variant	1/5	1	NM_001040436.3	ENSP00000320658	P1
YARS2	ENST00000548490.1 linkuse as main transcript	c.494G>T	p.Gly165Val	missense_variant, NMD_transcript_variant	1/5	5		ENSP00000447710

Frequencies

GnomAD3 genomes

AF:

0.141

AC:

21485

AN:

152048

Hom.:

1552

Cov.:

show subpopulations

Gnomad AFR

AF:

0.169

Gnomad AMI

AF:

0.276

Gnomad AMR

AF:

0.122

Gnomad ASJ

AF:

0.160

Gnomad EAS

AF:

0.0749

Gnomad SAS

AF:

0.105

Gnomad FIN

AF:

0.0892

Gnomad MID

AF:

0.182

Gnomad NFE

AF:

0.141

Gnomad OTH

AF:

0.152

GnomAD3 exomes

AF:

0.123

AC:

30883

AN:

250954

Hom.:

2031

AF XY:

0.125

AC XY:

17035

AN XY:

135816

show subpopulations

Gnomad AFR exome

AF:

0.171

Gnomad AMR exome

AF:

0.0778

Gnomad ASJ exome

AF:

0.168

Gnomad EAS exome

AF:

0.0773

Gnomad SAS exome

AF:

0.111

Gnomad FIN exome

AF:

0.0974

Gnomad NFE exome

AF:

0.141

Gnomad OTH exome

AF:

0.134

GnomAD4 exome

AF:

0.134

AC:

196140

AN:

1461796

Hom.:

13548

Cov.:

AF XY:

0.134

AC XY:

97709

AN XY:

727200

show subpopulations

Gnomad4 AFR exome

AF:

0.175

Gnomad4 AMR exome

AF:

0.0837

Gnomad4 ASJ exome

AF:

0.162

Gnomad4 EAS exome

AF:

0.0747

Gnomad4 SAS exome

AF:

0.112

Gnomad4 FIN exome

AF:

0.100

Gnomad4 NFE exome

AF:

0.139

Gnomad4 OTH exome

AF:

0.139

GnomAD4 genome

AF:

0.141

AC:

21489

AN:

152166

Hom.:

1556

Cov.:

AF XY:

0.139

AC XY:

10331

AN XY:

74390

show subpopulations

Gnomad4 AFR

AF:

0.169

Gnomad4 AMR

AF:

0.122

Gnomad4 ASJ

AF:

0.160

Gnomad4 EAS

AF:

0.0751

Gnomad4 SAS

AF:

0.105

Gnomad4 FIN

AF:

0.0892

Gnomad4 NFE

AF:

0.141

Gnomad4 OTH

AF:

0.150

Alfa

AF:

0.142

Hom.:

940

Bravo

AF:

0.146

TwinsUK

AF:

0.138

AC:

510

ALSPAC

AF:

0.136

AC:

523

ESP6500AA

AF:

0.162

AC:

714

ESP6500EA

AF:

0.143

AC:

1231

ExAC

AF:

0.126

AC:

15241

Asia WGS

AF:

0.104

AC:

362

AN:

3478

EpiCase

AF:

0.149

EpiControl

AF:

0.153

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 30026338, 29300242, 26647310, 24344687) -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 22, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Myopathy, lactic acidosis, and sideroblastic anemia 2

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Dec 05, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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. -

Myopathy, lactic acidosis, and sideroblastic anemia

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.57

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.30

Eigen

Benign

-0.15

Eigen_PC

Benign

-0.041

FATHMM_MKL

Benign

0.045

LIST_S2

Uncertain

0.89

MetaRNN

Benign

0.0023

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.68

MutationTaster

Benign

1.5e-8

PrimateAI

Benign

0.36

PROVEAN

Benign

-2.0

REVEL

Benign

0.19

Sift

Benign

0.069

Sift4G

Uncertain

0.043

Polyphen

0.62

Vest4

0.13

MPC

0.60

ClinPred

0.060

GERP RS

4.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.64

gMVP

0.37

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