NM_004184.4:c.1255G>T

Variant names:

• chr14-100335036-C-A
• rs550196955
• NM_004184.4:c.1255G>T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PM5 PP3_Moderate

The NM_004184.4(WARS1):​c.1255G>T​(p.Asp419Tyr) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 2/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D419N) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: WARS1 NM_004184.4 missense, splice_region
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.77
• Publications: 3 publications found

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

ENSG00000258666 (HGNC:58289):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: 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.
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WARS1	NM_004184.4	c.1255G>T	p.Asp419Tyr	missense_variant, splice_region_variant	Exon 11 of 11	ENST00000392882.7	NP_004175.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WARS1	ENST00000392882.7	c.1255G>T	p.Asp419Tyr	missense_variant, splice_region_variant	Exon 11 of 11	1	NM_004184.4	ENSP00000376620.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Pathogenic	34
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.51	D;.;D;.;D;.
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	.;.;.;.;D;D
M_CAP	Uncertain	0.18	D
MetaRNN	Uncertain	0.48	T;T;T;T;T;T
MetaSVM	Uncertain	0.51	D
MutationAssessor	Uncertain	2.8	M;.;M;.;M;.
PhyloP100		7.8
PrimateAI	Benign	0.43	T
PROVEAN	Pathogenic	-4.9	D;D;D;D;D;D
REVEL	Pathogenic	0.73
Sift	Uncertain	0.0020	D;D;D;D;D;D
Sift4G	Uncertain	0.018	D;D;D;D;D;D
Polyphen		0.99	D;.;D;.;D;.
Vest4		0.35
MutPred		0.55		Gain of catalytic residue at A424 (P = 0.0022);.;Gain of catalytic residue at A424 (P = 0.0022);.;Gain of catalytic residue at A424 (P = 0.0022);.;
MVP		0.52
MPC		1.4
ClinPred		0.99	D
GERP RS		5.2
Varity_R		0.89
gMVP		0.83
Mutation Taster		=24/76	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.98
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

Other links and lift over

dbSNP: rs550196955; hg19: chr14-100801373;