14-100335036-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PP5_ModerateBS2_Supporting

The NM_004184.4(WARS1):c.1255G>A(p.Asp419Asn) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000242 in 1,613,060 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★).

Frequency

Genomes: 𝑓 0.000099 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00026 ( 4 hom. )

Consequence

WARS1
NM_004184.4 missense, splice_region

Scores

Splicing: ADA: 0.9991

Clinical Significance

Likely pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 7.77

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 links:

ENSG00000258666 (HGNC:58289):

ENSG00000258666 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PP5

Variant 14-100335036-C-T is Pathogenic according to our data. Variant chr14-100335036-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2499496.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High AC in GnomAd4 at 15 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WARS1	NM_004184.4 link	c.1255G>A	p.Asp419Asn	missense_variant, splice_region_variant	Exon 11 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.1255G>A	p.Asp419Asn	missense_variant, splice_region_variant	Exon 11 of 11	1	NM_004184.4	ENSP00000376620.2		P23381-1

Frequencies

GnomAD3 genomes

AF:

0.0000986

AC:

AN:

152144

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00186

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000435

AC:

108

AN:

248198

Hom.:

AF XY:

0.000625

AC XY:

AN XY:

134394

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00334

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000361

Gnomad OTH exome

AF:

0.000329

GnomAD4 exome

AF:

0.000257

AC:

376

AN:

1460798

Hom.:

Cov.:

AF XY:

0.000381

AC XY:

277

AN XY:

726568

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00365

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000315

Gnomad4 OTH exome

AF:

0.000249

GnomAD4 genome

AF:

0.0000985

AC:

AN:

152262

Hom.:

Cov.:

AF XY:

0.000134

AC XY:

AN XY:

74452

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00186

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000844

Hom.:

Bravo

AF:

0.0000491

ExAC

AF:

0.000428

AC:

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Neurodevelopmental disorder with microcephaly and speech delay, with or without brain abnormalities

Pathogenic:2

Aug 04, 2023

3billion

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.039%). Predicted Consequence/Location: Missense changes are a common disease-causing mechanism. Functional studies provide moderate evidence of the variant having a damaging effect on the gene or gene product (PMID: 35815345). In silico tool predictions suggest no damaging effect of the variant on gene or gene product [REVEL: 0.30 (<0.4); 3Cnet: 0.07 (<0.15, specificity 0.78 and negative predicitive value 0.92)]. Same nucleotide change resulting in same amino acid change has been previously reported to be associated with WARS1 related disorder (ClinVar ID: VCV002499496 /PMID: 35815345). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. -

Apr 19, 2023

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.37

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.35

T;.;T;.;T;.

Eigen

Uncertain

0.25

Eigen_PC

Uncertain

0.34

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Pathogenic

0.99

.;.;.;.;D;D

M_CAP

Uncertain

0.092

MetaRNN

Benign

0.017

T;T;T;T;T;T

MetaSVM

Uncertain

-0.22

MutationAssessor

Benign

1.5

L;.;L;.;L;.

PrimateAI

Benign

0.43

PROVEAN

Benign

-1.9

N;N;N;N;N;N

REVEL

Uncertain

0.30

Sift

Benign

0.050

D;T;D;T;D;T

Sift4G

Benign

0.12

T;T;T;T;T;T

Polyphen

0.018

B;.;B;.;B;.

Vest4

0.21

MutPred

0.49

Gain of catalytic residue at A424 (P = 0.0013);.;Gain of catalytic residue at A424 (P = 0.0013);.;Gain of catalytic residue at A424 (P = 0.0013);.;

MVP

0.72

MPC

0.46

ClinPred

0.10

GERP RS

5.2

Varity_R

0.52

gMVP

0.68

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.95

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over