chr12-32755771-G-T

Position:

chr12-32755771-G-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_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. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

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

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:

ENSG00000286950 (HGNC:):

ENSG00000286950 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

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 id is 215417.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1, Benign=3}.

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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 41 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
YARS2	NM_001040436.3 linkuse as main transcript	c.104C>A	p.Ala35Asp	missense_variant	1/5	ENST00000324868.13	NP_001035526.1	Q9Y2Z4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
YARS2	ENST00000324868.13 linkuse as main transcript	c.104C>A	p.Ala35Asp	missense_variant	1/5	1	NM_001040436.3	ENSP00000320658.8	Q9Y2Z4
YARS2	ENST00000548490.1 linkuse as main transcript	n.26C>A		non_coding_transcript_exon_variant	1/5	5		ENSP00000447710.1	H0YHS6
ENSG00000286950	ENST00000666291.1 linkuse as main transcript	n.262G>T		non_coding_transcript_exon_variant	1/1

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

GnomAD3 exomes

AF:

0.00380

AC:

953

AN:

250920

Hom.:

AF XY:

0.00457

AC XY:

621

AN XY:

135810

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 SAS exome

AF:

0.0176

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

Gnomad4 AFR exome

AF:

0.00149

Gnomad4 AMR exome

AF:

0.000715

Gnomad4 ASJ exome

AF:

0.00582

Gnomad4 EAS exome

AF:

0.000731

Gnomad4 SAS exome

AF:

0.0166

Gnomad4 FIN exome

AF:

0.000696

Gnomad4 NFE exome

AF:

0.00212

Gnomad4 OTH exome

AF:

0.00417

GnomAD4 genome

AF:

0.00209

AC:

319

AN:

152366

Hom.:

Cov.:

AF XY:

0.00228

AC XY:

170

AN XY:

74496

show subpopulations

Gnomad4 AFR

AF:

0.000817

Gnomad4 AMR

AF:

0.000784

Gnomad4 ASJ

AF:

0.00576

Gnomad4 EAS

AF:

0.000580

Gnomad4 SAS

AF:

0.0180

Gnomad4 FIN

AF:

0.000283

Gnomad4 NFE

AF:

0.00220

Gnomad4 OTH

AF:

0.00189

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

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Sep 18, 2017	- -

Hereditary Sideroblastic Anemia with Myopathy and Lactic Acidosis

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 12, 2015

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

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. -

YARS2-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 13, 2019

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

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

PrimateAI

Benign

0.34

PROVEAN

Benign

-1.4

REVEL

Benign

0.11

Sift

Benign

0.060

Sift4G

Benign

0.45

Polyphen

0.0010

Vest4

0.29

MVP

0.39

MPC

0.71

ClinPred

0.0043

GERP RS

0.80

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.12

gMVP

0.45

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