rs587777213

Variant names:

• chr12-32755738-C-T
• rs587777213
• NM_001040436.3:c.137G>A

Your query was ambiguous. Multiple possible variants found:

• chr12-32755738-C-T
• chr12-32755738-C-A

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PS3 PM2 PP2 PP3_Moderate PP5_Moderate

The NM_001040436.3(YARS2):​c.137G>A​(p.Gly46Asp) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,692 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). ClinVar reports functional evidence for this variant: "SCV000322298: Immunoblot analysis for one of these individuals demonstrated that the G46D variant generates undetectable levels of YARS2 protein in myoblasts and myotubes and results in a generalized mitochondrial translation defect (Sasarman et al., 2012).".

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: YARS2 NM_001040436.3 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 7.08
• Publications: 11 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: Pathogenic. The variant received 11 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000322298: Immunoblot analysis for one of these individuals demonstrated that the G46D variant generates undetectable levels of YARS2 protein in myoblasts and myotubes and results in a generalized mitochondrial translation defect (Sasarman et al., 2012).
• PM2: Very rare variant in population databases, with high coverage
• 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 2, myopathy, lactic acidosis, and sideroblastic anemia.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.908
• PP5: Variant 12-32755738-C-T is Pathogenic according to our data. Variant chr12-32755738-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 102433.Status of the report is criteria_provided_single_submitter, 1 stars.

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.137G>A	p.Gly46Asp	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.137G>A	p.Gly46Asp	missense	Exon 1 of 5	ENSP00000320658.8	Q9Y2Z4
	YARS2	ENST00000874023.1		c.137G>A	p.Gly46Asp	missense	Exon 1 of 4	ENSP00000544082.1
	YARS2	ENST00000874022.1		c.137G>A	p.Gly46Asp	missense	Exon 1 of 4	ENSP00000544081.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251294 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461692 Hom.: 0 Cov.: 33 AF XY: 0.00000413 AC XY: 3 AN XY: 727160

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53262

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111970

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000427 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.44
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.27
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.74	D
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.059	D
MetaRNN	Pathogenic	0.91	D
MetaSVM	Uncertain	-0.21	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		7.1
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-4.5	D
REVEL	Pathogenic	0.68
Sift	Benign	0.046	D
Sift4G	Uncertain	0.039	D
Polyphen		1.0	D
Vest4		0.97
MutPred		0.70		Loss of methylation at R45 (P = 0.0465)
MVP		0.83
MPC		1.3
ClinPred		1.0	D
GERP RS		5.1
PromoterAI		0.069	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.82
gMVP		0.79
Mutation Taster		=13/87	disease causing (ClinVar)

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: rs587777213; hg19: chr12-32908672;