1-32797768-C-T

Variant names:

• chr1-32797768-C-T
• rs121908834
• NM_003680.4:c.586G>A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_003680.4(YARS1):​c.586G>A​(p.Glu196Lys) variant causes a missense change involving the alteration of a 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E196G) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: YARS1 NM_003680.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3 U:1
• Conservation: PhyloP100: 7.43

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 Pathogenic. Variant got 18 ACMG points.

• PM1: In a helix (size 9) in uniprot entity SYYC_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_003680.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-32797768-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 243071.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.947
• PP5: Variant 1-32797768-C-T is Pathogenic according to our data. Variant chr1-32797768-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 6189.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-32797768-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
YARS1	NM_003680.4	c.586G>A	p.Glu196Lys	missense_variant	Exon 5 of 13	ENST00000373477.9	NP_003671.1
YARS1	XM_011542347.3	c.-45G>A		5_prime_UTR_variant	Exon 3 of 11		XP_011540649.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
YARS1	ENST00000373477.9	c.586G>A	p.Glu196Lys	missense_variant	Exon 5 of 13	1	NM_003680.4	ENSP00000362576.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Charcot-Marie-Tooth disease dominant intermediate C Pathogenic:2

Feb 01, 2006

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Mar 13, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt YARS protein function. For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Glu196 amino acid residue in YARS. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 26257172). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects YARS function (PMID: 19561293, 26138142, 26975778). ClinVar contains an entry for this variant (Variation ID: 6189). This missense change has been observed in individual(s) with dominant intermediate Charcot-Marie-Tooth disease, type C (PMID: 14606043, 16429158). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 196 of the YARS protein (p.Glu196Lys). -

Neurologic, endocrine, and pancreatic disease, multisystem, infantile-onset 2 Pathogenic:1

Sep 15, 2023

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Charcot-Marie-Tooth disease Uncertain:1

-

Inherited Neuropathy Consortium

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.73
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.23
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.39	T;T
Eigen	Pathogenic	0.69
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Benign	0.077	D
MetaRNN	Pathogenic	0.95	D;D
MetaSVM	Uncertain	-0.27	T
MutationAssessor	Benign	1.6	L;.
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-3.4	D;.
REVEL	Uncertain	0.63
Sift	Benign	0.16	T;.
Sift4G	Benign	0.36	T;T
Polyphen		1.0	D;.
Vest4		0.83
MutPred		0.90		Gain of MoRF binding (P = 0.0043);Gain of MoRF binding (P = 0.0043);
MVP		0.92
MPC		1.2
ClinPred		0.98	D
GERP RS		4.9
Varity_R		0.76
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: rs121908834; hg19: chr1-33263369;