rs587777215

Variant names:

• chr12-32747335-T-C
• rs587777215
• NM_001040436.3:c.1303A>G

Your query was ambiguous. Multiple possible variants found:

• chr12-32747335-T-C
• chr12-32747335-T-G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM2 PP2 PP5 BP4

The NM_001040436.3(YARS2):​c.1303A>G​(p.Ser435Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: YARS2 NM_001040436.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 3.73
• Publications: 3 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, Labcorp Genetics (formerly Invitae), G2P
• myopathy, lactic acidosis, and sideroblastic anemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• 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, myopathy, lactic acidosis, and sideroblastic anemia 2.
• PP5: Variant 12-32747335-T-C is Pathogenic according to our data. Variant chr12-32747335-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 102436.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.38722578). . Strength limited to SUPPORTING due to the PP5.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	YARS2	NM_001040436.3	MANE Select	c.1303A>G	p.Ser435Gly	missense	Exon 5 of 5	NP_001035526.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	YARS2	ENST00000324868.13	TSL:1 MANE Select	c.1303A>G	p.Ser435Gly	missense	Exon 5 of 5	ENSP00000320658.8
	YARS2	ENST00000548490.1	TSL:5	n.*314A>G		non_coding_transcript_exon	Exon 5 of 5	ENSP00000447710.1
	YARS2	ENST00000551673.5	TSL:5	n.200A>G		non_coding_transcript_exon	Exon 2 of 3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Myopathy, lactic acidosis, and sideroblastic anemia 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Uncertain	0.026	T
BayesDel_noAF	Benign	-0.20
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.36	T
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.075	D
MetaRNN	Benign	0.39	T
MetaSVM	Benign	-0.44	T
MutationAssessor	Pathogenic	3.1	M
PhyloP100		3.7
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-1.5	N
REVEL	Pathogenic	0.74
Sift	Benign	0.21	T
Sift4G	Benign	0.26	T
Polyphen		0.79	P
Vest4		0.34
MutPred		0.44		Loss of sheet (P = 0.0817)
MVP		0.75
MPC		0.56
ClinPred		0.93	D
GERP RS		5.7
Varity_R		0.079
gMVP		0.38
Mutation Taster		=34/66	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: rs587777215; hg19: chr12-32900269;