rs11539445

Variant names:

• chr12-32755303-C-A
• rs11539445
• NM_001040436.3:c.572G>T

Your query was ambiguous. Multiple possible variants found:

• chr12-32755303-C-A
• chr12-32755303-C-T

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 3P and 20B. PM5 PP2 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. 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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 3.46
• Publications: 37 publications found

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, G2P, Labcorp Genetics (formerly Invitae)
• myopathy, lactic acidosis, and sideroblastic anemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000286950 (HGNC:):

ACMG classification

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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001040436.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	YARS2	NM_001040436.3	MANE Select	c.572G>T	p.Gly191Val	missense	Exon 1 of 5	NP_001035526.1	Q9Y2Z4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	YARS2	ENST00000324868.13	TSL:1 MANE Select	c.572G>T	p.Gly191Val	missense	Exon 1 of 5	ENSP00000320658.8	Q9Y2Z4
	YARS2	ENST00000874023.1		c.572G>T	p.Gly191Val	missense	Exon 1 of 4	ENSP00000544082.1
	YARS2	ENST00000874022.1		c.572G>T	p.Gly191Val	missense	Exon 1 of 4	ENSP00000544081.1

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

GnomAD2 exomes AF: 0.123 AC: 30883 AN: 250954 AF XY: 0.125

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

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

GnomAD4 genome AF: 0.141 AC: 21489 AN: 152166 Hom.: 1556 Cov.: 32 AF XY: 0.139 AC XY: 10331 AN XY: 74390

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: 53 AN: 292

European-Non Finnish (NFE) AF: 0.141 AC: 9590 AN: 67984

Other (OTH) AF: 0.150 AC: 317 AN: 2112

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

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	2	Myopathy, lactic acidosis, and sideroblastic anemia 2 (2)
-	-	1	Myopathy, lactic acidosis, and sideroblastic anemia (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		3.5
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
Mutation Taster		=72/28	polymorphism (auto)

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

Other links and lift over

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