rs786205442

chr1-32786971-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Moderate PP5_Moderate

The NM_003680.4(YARS1):c.789C>A(p.Phe263Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: YARS1 NM_003680.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 2.68

Genes affected

YARS1 (HGNC:12840): (tyrosyl-tRNA synthetase 1) Aminoacyl-tRNA synthetases catalyze the aminoacylation of tRNA by their cognate amino acid. Because of their central role in linking amino acids with nucleotide triplets contained in tRNAs, aminoacyl-tRNA synthetases are thought to be among the first proteins that appeared in evolution. Tyrosyl-tRNA synthetase belongs to the class I tRNA synthetase family. Cytokine activities have also been observed for the human tyrosyl-tRNA synthetase, after it is split into two parts, an N-terminal fragment that harbors the catalytic site and a C-terminal fragment found only in the mammalian enzyme. The N-terminal fragment is an interleukin-8-like cytokine, whereas the released C-terminal fragment is an EMAP II-like cytokine. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.844
• PP5: Variant 1-32786971-G-T is Pathogenic according to our data. Variant chr1-32786971-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 190979.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
YARS1	NM_003680.4	c.789C>A	p.Phe263Leu	missense_variant	7/13	ENST00000373477.9
YARS1	XM_011542347.3	c.159C>A	p.Phe53Leu	missense_variant	5/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
YARS1	ENST00000373477.9	c.789C>A	p.Phe263Leu	missense_variant	7/13	1	NM_003680.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Department Of Translational Genomics (developmental Genetics Section), King Faisal Specialist Hospital & Research Centre

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Uncertain	0.050	T
BayesDel_noAF	Benign	-0.17
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Benign	0.39	T;T
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.84	D;D
MetaSVM	Uncertain	-0.27	T
MutationAssessor	Benign	1.9	L;.
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-5.4	D;.
REVEL	Uncertain	0.53
Sift	Benign	0.097	T;.
Sift4G	Benign	0.14	T;T
Polyphen		1.0	D;.
Vest4		0.92
MutPred		0.66		Loss of helix (P = 0.1299);Loss of helix (P = 0.1299);
MVP		0.83
MPC		1.2
ClinPred		1.0	D
GERP RS		4.4
Varity_R		0.92
gMVP		0.68

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.30		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.30		Position offset: -31

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs786205442; hg19: chr1-33252572;