rs141955005

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_003680.4(YARS1):c.1348C>T(p.Arg450Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000997 in 1,614,082 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R450H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000099 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00010 ( 0 hom. )

Consequence

YARS1
NM_003680.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 4.04

Publications

1 publications found

Variant links:

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)

YARS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.21146762).

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.1348C>T	p.Arg450Cys	missense	Exon 12 of 13	NP_003671.1	P54577

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
YARS1	ENST00000373477.9	TSL:1 MANE Select	c.1348C>T	p.Arg450Cys	missense	Exon 12 of 13	ENSP00000362576.4	P54577
YARS1	ENST00000906066.1		c.1435C>T	p.Arg479Cys	missense	Exon 13 of 14	ENSP00000576125.1
YARS1	ENST00000918766.1		c.1345C>T	p.Arg449Cys	missense	Exon 12 of 13	ENSP00000588825.1

Frequencies

GnomAD3 genomes

AF:

0.0000986

AC:

AN:

152190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000191

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000398

AC:

AN:

251398

AF XY:

0.0000221

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000109

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000616

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000999

AC:

146

AN:

1461892

Hom.:

Cov.:

AF XY:

0.000100

AC XY:

AN XY:

727246

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000120

AC:

133

AN:

1112012

Other (OTH)

AF:

0.000199

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.462

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000986

AC:

AN:

152190

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74352

show subpopulations

African (AFR)

AF:

0.0000483

AC:

AN:

41448

American (AMR)

AF:

0.00

AC:

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000191

AC:

AN:

68038

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000165

Hom.:

Bravo

AF:

0.0000907

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.0000330

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Charcot-Marie-Tooth disease dominant intermediate C (1)

Inborn genetic diseases (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.22

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.28

Eigen

Uncertain

0.25

Eigen_PC

Uncertain

0.39

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.90

M_CAP

Benign

0.025

MetaRNN

Benign

0.21

MetaSVM

Benign

-0.65

MutationAssessor

Benign

0.58

PhyloP100

4.0

PrimateAI

Benign

0.42

PROVEAN

Benign

-2.1

REVEL

Benign

0.27

Sift

Benign

0.063

Sift4G

Uncertain

0.045

Polyphen

0.41

Vest4

0.29

MVP

0.82

MPC

0.47

ClinPred

0.087

GERP RS

5.7

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.7

Varity_R

0.21

gMVP

0.51

Mutation Taster

=35/65

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over