rs11539445

chr12-32755303-C-Achr12-32755303-C-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM5 BP4_Strong BP6_Very_Strong BA1

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 (★★). 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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 3.46

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]

ACMG classification

Verdict is Benign. Variant got -18 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 id is 102434.Status of the report is no_assertion_criteria_provided, 0 stars.
• 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	UniProt
YARS2	NM_001040436.3	c.572G>T	p.Gly191Val	missense_variant	1/5	ENST00000324868.13

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.141 AC: 21485 AN: 152048 Hom.: 1552 Cov.: 32

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

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.: 34 AF XY: 0.134 AC XY: 97709 AN XY: 727200

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.: 32 AF XY: 0.139 AC XY: 10331 AN XY: 74390

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:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 22, 2016	- -
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, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

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	T
BayesDel_noAF	Benign	-0.57
Cadd	Uncertain	24
Dann	Uncertain	0.99
DEOGEN2	Benign	0.30	T
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.041
FATHMM_MKL	Benign	0.045	N
LIST_S2	Uncertain	0.89	D
MetaRNN	Benign	0.0023	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.68	N
MutationTaster	Benign	1.5e-8	P
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.19
Sift	Benign	0.069	T
Sift4G	Uncertain	0.043	D
Polyphen		0.62	P
Vest4		0.13
MPC		0.60
ClinPred		0.060	T
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

Other links and lift over

dbSNP: rs11539445; hg19: chr12-32908237; COSMIC: COSV61401578;