chr14-100342508-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_StrongBA1

The NM_004184.4(WARS1):c.1003C>T(p.Leu335Leu) variant causes a synonymous change. The variant allele was found at a frequency of 0.735 in 1,613,524 control chromosomes in the GnomAD database, including 438,903 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.68 ( 36764 hom., cov: 30)

Exomes 𝑓: 0.74 ( 402139 hom. )

Consequence

WARS1
NM_004184.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 4.08

Publications

35 publications found

Variant links:

Genes affected

WARS1 (HGNC:12729): (tryptophanyl-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. Two forms of tryptophanyl-tRNA synthetase exist, a cytoplasmic form, named WARS, and a mitochondrial form, named WARS2. Tryptophanyl-tRNA synthetase (WARS) catalyzes the aminoacylation of tRNA(trp) with tryptophan and is induced by interferon. Tryptophanyl-tRNA synthetase belongs to the class I tRNA synthetase family. Four transcript variants encoding two different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

WARS1 Gene-Disease associations (from GenCC):

distal hereditary motor neuropathy
Inheritance: AD Classification: DEFINITIVE, LIMITED Submitted by: G2P, ClinGen
neuronopathy, distal hereditary motor, type 9
Inheritance: AD Classification: STRONG, MODERATE Submitted by: Broad Center for Mendelian Genomics, Labcorp Genetics (formerly Invitae)
neurodevelopmental disorder with microcephaly and speech delay, with or without brain abnormalities
Inheritance: AR Classification: LIMITED Submitted by: G2P

WARS1 links:

ENSG00000258666 (HGNC:58289):

ENSG00000258666 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -16 ACMG points.

BP6

Variant 14-100342508-G-A is Benign according to our data. Variant chr14-100342508-G-A is described in ClinVar as Benign. ClinVar VariationId is 1265241.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.795 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WARS1	NM_004184.4 link	c.1003C>T	p.Leu335Leu	synonymous_variant	Exon 9 of 11	ENST00000392882.7	NP_004175.2	P23381-1A0A024R6K8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WARS1	ENST00000392882.7 link	c.1003C>T	p.Leu335Leu	synonymous_variant	Exon 9 of 11	1	NM_004184.4	ENSP00000376620.2		P23381-1

Frequencies

GnomAD3 genomes

AF:

0.684

AC:

103899

AN:

151816

Hom.:

36739

Cov.:

show subpopulations

Gnomad AFR

AF:

0.493

Gnomad AMI

AF:

0.580

Gnomad AMR

AF:

0.807

Gnomad ASJ

AF:

0.816

Gnomad EAS

AF:

0.780

Gnomad SAS

AF:

0.806

Gnomad FIN

AF:

0.774

Gnomad MID

AF:

0.725

Gnomad NFE

AF:

0.736

Gnomad OTH

AF:

0.732

GnomAD2 exomes

AF:

0.757

AC:

190105

AN:

251292

AF XY:

0.760

show subpopulations

Gnomad AFR exome

AF:

0.494

Gnomad AMR exome

AF:

0.857

Gnomad ASJ exome

AF:

0.810

Gnomad EAS exome

AF:

0.786

Gnomad FIN exome

AF:

0.774

Gnomad NFE exome

AF:

0.737

Gnomad OTH exome

AF:

0.767

GnomAD4 exome

AF:

0.740

AC:

1081416

AN:

1461590

Hom.:

402139

Cov.:

AF XY:

0.742

AC XY:

539625

AN XY:

727096

show subpopulations

African (AFR)

AF:

0.486

AC:

16266

AN:

33470

American (AMR)

AF:

0.850

AC:

38015

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.812

AC:

21205

AN:

26130

East Asian (EAS)

AF:

0.777

AC:

30841

AN:

39696

South Asian (SAS)

AF:

0.804

AC:

69319

AN:

86246

European-Finnish (FIN)

AF:

0.778

AC:

41569

AN:

53404

Middle Eastern (MID)

AF:

0.775

AC:

4379

AN:

5650

European-Non Finnish (NFE)

AF:

0.733

AC:

815133

AN:

1111908

Other (OTH)

AF:

0.740

AC:

44689

AN:

60368

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

15812

31624

47436

63248

79060

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

20106

40212

60318

80424

100530

<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:

0.684

AC:

103962

AN:

151934

Hom.:

36764

Cov.:

AF XY:

0.691

AC XY:

51334

AN XY:

74258

show subpopulations

African (AFR)

AF:

0.493

AC:

20401

AN:

41402

American (AMR)

AF:

0.807

AC:

12342

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.816

AC:

2830

AN:

3470

East Asian (EAS)

AF:

0.780

AC:

3995

AN:

5122

South Asian (SAS)

AF:

0.806

AC:

3880

AN:

4816

European-Finnish (FIN)

AF:

0.774

AC:

8189

AN:

10580

Middle Eastern (MID)

AF:

0.738

AC:

217

AN:

294

European-Non Finnish (NFE)

AF:

0.736

AC:

50032

AN:

67942

Other (OTH)

AF:

0.734

AC:

1547

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1555

3110

4664

6219

7774

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

816

1632

2448

3264

4080

<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:

0.719

Hom.:

106537

Bravo

AF:

0.680

Asia WGS

AF:

0.778

AC:

2708

AN:

3478

EpiCase

AF:

0.744

EpiControl

AF:

0.747

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

May 05, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

WARS1-related disorder

Benign:1

Oct 17, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Neuronopathy, distal hereditary motor, type 9

Benign:1

Dec 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.44

CADD

Benign

(source)

DANN

Benign

0.91

PhyloP100

4.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=95/5

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.26

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.26

Position offset: -22

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over