rs587777213

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

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

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PM5 PP2 PP3_Moderate

The NM_001040436.3(YARS2):​c.137G>T​(p.Gly46Val) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,692 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G46D) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: YARS2 NM_001040436.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.08

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]

ENSG00000286950 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr12-32755738-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 102433.Status of the report is criteria_provided_single_submitter, 1 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.931

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
YARS2	NM_001040436.3	c.137G>T	p.Gly46Val	missense_variant	Exon 1 of 5	ENST00000324868.13	NP_001035526.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
YARS2	ENST00000324868.13	c.137G>T	p.Gly46Val	missense_variant	Exon 1 of 5	1	NM_001040436.3	ENSP00000320658.8
YARS2	ENST00000548490.1	n.59G>T		non_coding_transcript_exon_variant	Exon 1 of 5	5		ENSP00000447710.1
ENSG00000286950	ENST00000666291.1	n.229C>A		non_coding_transcript_exon_variant	Exon 1 of 1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461692 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727160

Gnomad4 AFR exome AF: 0.00 AC: 0 AN: 33480

Gnomad4 AMR exome AF: 0.00 AC: 0 AN: 44724

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 26136

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39700

Gnomad4 SAS exome AF: 0.00 AC: 0 AN: 86258

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 53262

Gnomad4 NFE exome AF: 8.99e-7 AC: 1 AN: 1111970

Gnomad4 Remaining exome AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.69
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.78	D
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.82	T
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Uncertain	0.0043	D
MutationAssessor	Uncertain	2.4	M
PrimateAI	Uncertain	0.61	T
PROVEAN	Pathogenic	-6.5	D
REVEL	Pathogenic	0.74
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.94
MutPred		0.75		Loss of ubiquitination at K43 (P = 0.0603);
MVP		0.88
MPC		1.5
ClinPred		1.0	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.95
gMVP		0.84
Mutation Taster		=14/86	disease causing

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: rs587777213; hg19: chr12-32908672;