chr12-32755303-C-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 3P and 20B. PM5PP2BP4_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. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G191D) has been classified as Pathogenic.

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

Publications

37 publications found

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 Gene-Disease associations (from GenCC):

myopathy, lactic acidosis, and sideroblastic anemia 2
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
myopathy, lactic acidosis, and sideroblastic anemia
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

YARS2 links:

ENSG00000286950 (HGNC:):

ENSG00000286950 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -17 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr12-32755303-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 102434.Status of the report is no_assertion_criteria_provided, 0 stars.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 13 curated pathogenic missense variants (we use a threshold of 10). The gene has 3 curated benign missense variants. Gene score misZ: 0.26421 (below the threshold of 3.09). Trascript score misZ: 0.56393 (below the threshold of 3.09). GenCC associations: The gene is linked to myopathy, lactic acidosis, and sideroblastic anemia, myopathy, lactic acidosis, and sideroblastic anemia 2.

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 Benign/Likely_benign. ClinVar VariationId is 308460.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 rank	MANE	Protein	UniProt
YARS2	NM_001040436.3 link	c.572G>T	p.Gly191Val	missense_variant	Exon 1 of 5	ENST00000324868.13	NP_001035526.1	Q9Y2Z4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
YARS2	ENST00000324868.13 link	c.572G>T	p.Gly191Val	missense_variant	Exon 1 of 5	1	NM_001040436.3	ENSP00000320658.8	Q9Y2Z4
YARS2	ENST00000548490.1 link	n.494G>T		non_coding_transcript_exon_variant	Exon 1 of 5	5		ENSP00000447710.1	H0YHS6
ENSG00000286950	ENST00000666291.1 link	n.-207C>A		upstream_gene_variant

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

GnomAD2 exomes

AF:

0.123

AC:

30883

AN:

250954

AF XY:

0.125

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 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

African (AFR)

AF:

0.175

AC:

5875

AN:

33480

American (AMR)

AF:

0.0837

AC:

3743

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.162

AC:

4242

AN:

26136

East Asian (EAS)

AF:

0.0747

AC:

2967

AN:

39700

South Asian (SAS)

AF:

0.112

AC:

9632

AN:

86256

European-Finnish (FIN)

AF:

0.100

AC:

5339

AN:

53328

Middle Eastern (MID)

AF:

0.180

AC:

1039

AN:

5768

European-Non Finnish (NFE)

AF:

0.139

AC:

154892

AN:

1112008

Other (OTH)

AF:

0.139

AC:

8411

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

12394

24788

37181

49575

61969

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

5508

11016

16524

22032

27540

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.141

AC:

21489

AN:

152166

Hom.:

1556

Cov.:

AF XY:

0.139

AC XY:

10331

AN XY:

74390

show subpopulations

African (AFR)

AF:

0.169

AC:

7017

AN:

41514

American (AMR)

AF:

0.122

AC:

1867

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.160

AC:

556

AN:

3468

East Asian (EAS)

AF:

0.0751

AC:

387

AN:

5152

South Asian (SAS)

AF:

0.105

AC:

505

AN:

4828

European-Finnish (FIN)

AF:

0.0892

AC:

946

AN:

10610

Middle Eastern (MID)

AF:

0.182

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.141

AC:

9590

AN:

67984

Other (OTH)

AF:

0.150

AC:

317

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

927

1855

2782

3710

4637

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

236

472

708

944

1180

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.143

Hom.:

1804

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

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 22, 2016

Mayo Clinic Laboratories, Mayo Clinic

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 30026338, 29300242, 26647310, 24344687) -

Myopathy, lactic acidosis, and sideroblastic anemia 2

Benign:2

Dec 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

(source)

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

PhyloP100

3.5

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

Mutation Taster

=72/28

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over