NM_003680.4:c.1573G>A

Variant names:

• chr1-32775995-C-T
• rs1553122256
• NM_003680.4:c.1573G>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3 PP5

The NM_003680.4(YARS1):​c.1573G>A​(p.Gly525Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,828 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 Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G525E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: YARS1 NM_003680.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.53
• Publications: 3 publications found

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]

YARS1 Gene-Disease associations (from GenCC):

• Charcot-Marie-Tooth disease

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• Charcot-Marie-Tooth disease dominant intermediate C

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
• neurologic, endocrine, and pancreatic disease, multisystem, infantile-onset 2

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.804
• PP5: Variant 1-32775995-C-T is Pathogenic according to our data. Variant chr1-32775995-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 446532.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003680.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	YARS1	NM_003680.4	MANE Select	c.1573G>A	p.Gly525Arg	missense	Exon 13 of 13	NP_003671.1	P54577

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	YARS1	ENST00000373477.9	TSL:1 MANE Select	c.1573G>A	p.Gly525Arg	missense	Exon 13 of 13	ENSP00000362576.4	P54577
	YARS1	ENST00000906066.1		c.1660G>A	p.Gly554Arg	missense	Exon 14 of 14	ENSP00000576125.1
	YARS1	ENST00000918766.1		c.1570G>A	p.Gly524Arg	missense	Exon 13 of 13	ENSP00000588825.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461828 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 727224

African (AFR) AF: 0.00 AC: 0 AN: 33476

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: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111976

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Neurologic, endocrine, and pancreatic disease, multisystem, infantile-onset 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.66
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.39	T
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.049	D
MetaRNN	Pathogenic	0.80	D
MetaSVM	Uncertain	0.072	D
MutationAssessor	Uncertain	2.8	M
PhyloP100		7.5
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-0.71	N
REVEL	Uncertain	0.43
Sift	Benign	0.053	T
Sift4G	Uncertain	0.059	T
Polyphen		1.0	D
Vest4		0.88
MutPred		0.43		Gain of solvent accessibility (P = 1e-04)
MVP		0.94
MPC		1.2
ClinPred		0.99	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.63
gMVP		0.76
Mutation Taster		=11/89	disease causing

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: rs1553122256; hg19: chr1-33241596;