14-100335036-C-T

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

2
6
11
Splicing: ADA: 0.9991
2

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]

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
WARS1NM_004184.4 linkc.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
WARS1ENST00000392882.7 linkc.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:
15
AN:
152144
Hom.:
0
Cov.:
33
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.:
0
AF XY:
0.000625
AC XY:
84
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.:
4
Cov.:
30
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:
15
AN:
152262
Hom.:
0
Cov.:
33
AF XY:
0.000134
AC XY:
10
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.:
0
Bravo
AF:
0.0000491
ExAC
AF:
0.000428
AC:
52
Asia WGS
AF:
0.00115
AC:
4
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
T
BayesDel_noAF
Benign
-0.37
CADD
Uncertain
25
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
D
LIST_S2
Pathogenic
0.99
.;.;.;.;D;D
M_CAP
Uncertain
0.092
D
MetaRNN
Benign
0.017
T;T;T;T;T;T
MetaSVM
Uncertain
-0.22
T
MutationAssessor
Benign
1.5
L;.;L;.;L;.
PrimateAI
Benign
0.43
T
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
T
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.

Other links and lift over

dbSNP: rs550196955; hg19: chr14-100801373; API