12-32755719-G-C

Variant names:

• chr12-32755719-G-C
• rs267607180
• NM_001040436.3:c.156C>G

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PP2 PP3 PP5_Very_Strong

The NM_001040436.3(YARS2):​c.156C>G​(p.Phe52Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000342 in 1,461,836 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 Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: YARS2 NM_001040436.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 4.94
• Publications: 12 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

ENSG00000286950 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• 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, 0.779
• PP5: Variant 12-32755719-G-C is Pathogenic according to our data. Variant chr12-32755719-G-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 1056.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
YARS2	NM_001040436.3	c.156C>G	p.Phe52Leu	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.156C>G	p.Phe52Leu	missense_variant	Exon 1 of 5	1	NM_001040436.3	ENSP00000320658.8
YARS2	ENST00000548490.1	n.78C>G		non_coding_transcript_exon_variant	Exon 1 of 5	5		ENSP00000447710.1
ENSG00000286950	ENST00000666291.1	n.210G>C		non_coding_transcript_exon_variant	Exon 1 of 1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251406 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: 0.00000342 AC: 5 AN: 1461836 Hom.: 0 Cov.: 33 AF XY: 0.00000550 AC XY: 4 AN XY: 727228

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: 53362

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5768

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1112012

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Myopathy, lactic acidosis, and sideroblastic anemia 2 Pathogenic:2

Dec 17, 2013

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Dec 03, 2018

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

The homozygous p.Phe52Leu variant in YARS2 was identified by our study in one individual with myopathy, lactic acidosis, and sideroblastic anemia. The p.Phe52Leu variant in YARS2 has been reported in 9 Lebanese individuals with myopathy, lactic acidosis, and sideroblastic anemia, segregated with disease in 4 affected relatives from 2 families (PMID: 24344687, 20598274, 23918765, 30026338), and was been identified in 0.0008957% (1/111650) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs267607180). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has been reported pathogenic in ClinVar (Variation ID: 1056). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In vitro functional studies provide some evidence that the p.Phe52Leu variant may impact protein function due to a deleterious effect on tRNATyr aminoacylation and mitochrondrial protein synthesis, which may explain the reduced levels of mitochondrial proteins in muscle cells from affected individuals (PMID: 20598274). However, these types of assays may not accurately represent biological function. In summary, although more studies are required to fully establish its clinical significance, the p.Phe52Leu variant is likely pathogenic. ACMG/AMP Criteria applied: PM2, PP1_Moderate, PS3 (Richards 2015). -

not provided Pathogenic:1

Jul 10, 2020

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Functional studies have demonstrated that F52L results in reduced mitochondrial tRNATyr aminoacylation activity and reduces the affinity of the mutant protein for tRNATyr, leading to reduced mitochondrial protein synthesis (Riley et al., 2010); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 20598274, 24344687, 23918765, 30026338) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.52	D
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Benign	0.76	D
LIST_S2	Benign	0.62	T
M_CAP	Benign	0.039	D
MetaRNN	Pathogenic	0.78	D
MetaSVM	Benign	-0.49	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		4.9
PrimateAI	Uncertain	0.65	T
PROVEAN	Pathogenic	-5.1	D
REVEL	Uncertain	0.50
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.013	D
Polyphen		1.0	D
Vest4		0.88
MutPred		0.39		Loss of methylation at K49 (P = 0.0814);
MVP		0.83
MPC		0.81
ClinPred		0.99	D
GERP RS		3.2
PromoterAI		-0.021	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.89
gMVP		0.67
Mutation Taster		=6/94	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: rs267607180; hg19: chr12-32908653;