12-32755771-G-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 1P and 13B. PP2BP4_StrongBP6BS1BS2

The NM_001040436.3(YARS2):c.104C>A(p.Ala35Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00292 in 1,613,946 control chromosomes in the GnomAD database, including 42 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict 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. A35T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0021 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0030 ( 41 hom. )

Consequence

YARS2
NM_001040436.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:5

Conservation

PhyloP100: 0.514

Publications

8 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 -12 ACMG points.

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=0.0041893423).

BP6

Variant 12-32755771-G-T is Benign according to our data. Variant chr12-32755771-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 215417.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00209 (319/152366) while in subpopulation SAS AF = 0.018 (87/4832). AF 95% confidence interval is 0.015. There are 1 homozygotes in GnomAd4. There are 170 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 41 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
YARS2	NM_001040436.3 link	c.104C>A	p.Ala35Asp	missense_variant	Exon 1 of 5	ENST00000324868.13	NP_001035526.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
YARS2	ENST00000324868.13 link	c.104C>A	p.Ala35Asp	missense_variant	Exon 1 of 5	1	NM_001040436.3	ENSP00000320658.8
YARS2	ENST00000548490.1 link	n.26C>A		non_coding_transcript_exon_variant	Exon 1 of 5	5		ENSP00000447710.1
ENSG00000286950	ENST00000666291.1 link	n.262G>T		non_coding_transcript_exon_variant	Exon 1 of 1

Frequencies

GnomAD3 genomes

AF:

0.00211

AC:

321

AN:

152248

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000820

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000785

Gnomad ASJ

AF:

0.00576

Gnomad EAS

AF:

0.000578

Gnomad SAS

AF:

0.0182

Gnomad FIN

AF:

0.000283

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.00222

Gnomad OTH

AF:

0.00191

GnomAD2 exomes

AF:

0.00380

AC:

953

AN:

250920

AF XY:

0.00457

show subpopulations

Gnomad AFR exome

AF:

0.000619

Gnomad AMR exome

AF:

0.000636

Gnomad ASJ exome

AF:

0.00656

Gnomad EAS exome

AF:

0.000435

Gnomad FIN exome

AF:

0.000601

Gnomad NFE exome

AF:

0.00238

Gnomad OTH exome

AF:

0.00392

GnomAD4 exome

AF:

0.00301

AC:

4396

AN:

1461580

Hom.:

Cov.:

AF XY:

0.00338

AC XY:

2458

AN XY:

727090

show subpopulations

African (AFR)

AF:

0.00149

AC:

AN:

33476

American (AMR)

AF:

0.000715

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00582

AC:

152

AN:

26136

East Asian (EAS)

AF:

0.000731

AC:

AN:

39698

South Asian (SAS)

AF:

0.0166

AC:

1433

AN:

86258

European-Finnish (FIN)

AF:

0.000696

AC:

AN:

53168

Middle Eastern (MID)

AF:

0.00850

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00212

AC:

2362

AN:

1111960

Other (OTH)

AF:

0.00417

AC:

252

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

291

581

872

1162

1453

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

104

208

312

416

520

<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:

0.00209

AC:

319

AN:

152366

Hom.:

Cov.:

AF XY:

0.00228

AC XY:

170

AN XY:

74496

show subpopulations

African (AFR)

AF:

0.000817

AC:

AN:

41600

American (AMR)

AF:

0.000784

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00576

AC:

AN:

3472

East Asian (EAS)

AF:

0.000580

AC:

AN:

5176

South Asian (SAS)

AF:

0.0180

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.000283

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.0204

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00220

AC:

150

AN:

68040

Other (OTH)

AF:

0.00189

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00235

Hom.:

Bravo

AF:

0.00169

TwinsUK

AF:

0.00135

AC:

ALSPAC

AF:

0.00234

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00209

AC:

ExAC

AF:

0.00399

AC:

484

Asia WGS

AF:

0.0150

AC:

AN:

3478

EpiCase

AF:

0.00240

EpiControl

AF:

0.00219

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:2

Sep 18, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Hereditary Sideroblastic Anemia with Myopathy and Lactic Acidosis

Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not specified

Benign:1

Jun 12, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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.

Myopathy, lactic acidosis, and sideroblastic anemia 2

Benign:1

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.

YARS2-related disorder

Benign:1

Jun 13, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.50

CADD

Benign

(source)

DANN

Benign

0.75

DEOGEN2

Benign

0.18

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.055

LIST_S2

Benign

0.44

MetaRNN

Benign

0.0042

MetaSVM

Benign

-0.92

MutationAssessor

Benign

1.7

PhyloP100

0.51

PrimateAI

Benign

0.34

PROVEAN

Benign

-1.4

REVEL

Benign

0.11

Sift

Benign

0.060

Sift4G

Benign

0.45

Vest4

0.29

ClinPred

0.0043

GERP RS

0.80

PromoterAI

0.090

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.12

gMVP

0.45

Mutation Taster

=98/2

polymorphism

(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