12-32755719-G-C

Position:

• chr12-32755719-G-C

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1 PM2 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

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]

(HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 13 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_001040436.3
• PM2: Very rare variant in population databases, with high coverage
• 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 [Likely_pathogenic]. Clinvar id is 1056.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-32755719-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
YARS2	NM_001040436.3	c.156C>G	p.Phe52Leu	missense_variant	1/5	ENST00000324868.13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
YARS2	ENST00000324868.13	c.156C>G	p.Phe52Leu	missense_variant	1/5	1	NM_001040436.3	P1
	ENST00000666291.1	n.210G>C		non_coding_transcript_exon_variant	1/1
YARS2	ENST00000548490.1	c.78C>G	p.Phe26Leu	missense_variant, NMD_transcript_variant	1/5	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251406 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135906

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 SAS 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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

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

Likely pathogenic, criteria provided, single submitter	research	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Dec 03, 2018	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). -
Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 17, 2013	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jul 10, 2020

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
MutationTaster	Benign	1.0	D
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
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.89
gMVP		0.67

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: rs267607180; hg19: chr12-32908653;