14-100342508-G-C

Variant names:

• chr14-100342508-G-C
• rs9453
• NM_004184.4:c.1003C>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_004184.4(WARS1):​c.1003C>G​(p.Leu335Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. L335L) has been classified as Benign.

• Frequency: Genomes: not found (cov: 30)
• Consequence: WARS1 NM_004184.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.08
• Publications: 35 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WARS1	NM_004184.4	c.1003C>G	p.Leu335Val	missense_variant	Exon 9 of 11	ENST00000392882.7	NP_004175.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WARS1	ENST00000392882.7	c.1003C>G	p.Leu335Val	missense_variant	Exon 9 of 11	1	NM_004184.4	ENSP00000376620.2

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 61

GnomAD4 genome Cov.: 30

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Uncertain	0.092	D
BayesDel_noAF	Benign	-0.11
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.17	T;.;T;.;T;.
Eigen	Benign	0.065
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.98	.;.;.;.;D;D
M_CAP	Benign	0.016	T
MetaRNN	Uncertain	0.44	T;T;T;T;T;T
MetaSVM	Benign	-0.64	T
MutationAssessor	Benign	1.6	L;.;L;.;L;.
PhyloP100		4.1
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-1.1	N;N;N;N;N;N
REVEL	Benign	0.16
Sift	Benign	0.082	T;T;T;T;T;T
Sift4G	Benign	0.12	T;T;T;T;T;T
Polyphen		0.063	B;.;B;.;B;.
Vest4		0.56
MutPred		0.52		Gain of catalytic residue at K331 (P = 0);.;Gain of catalytic residue at K331 (P = 0);.;Gain of catalytic residue at K331 (P = 0);.;
MVP		0.73
MPC		0.63
ClinPred		0.75	D
GERP RS		5.0
Varity_R		0.30
gMVP		0.61
Mutation Taster		=49/51	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
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

Other links and lift over

dbSNP: rs9453; hg19: chr14-100808845;