chr14-100342508-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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004184.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WARS1	NM_004184.4	MANE Select	c.1003C>G	p.Leu335Val	missense	Exon 9 of 11	NP_004175.2
	WARS1	NM_173701.2		c.1003C>G	p.Leu335Val	missense	Exon 9 of 11	NP_776049.1
	WARS1	NM_213645.2		c.880C>G	p.Leu294Val	missense	Exon 8 of 10	NP_998810.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WARS1	ENST00000392882.7	TSL:1 MANE Select	c.1003C>G	p.Leu335Val	missense	Exon 9 of 11	ENSP00000376620.2
	WARS1	ENST00000355338.6	TSL:1	c.1003C>G	p.Leu335Val	missense	Exon 9 of 11	ENSP00000347495.2
	WARS1	ENST00000557135.5	TSL:1	c.1003C>G	p.Leu335Val	missense	Exon 10 of 12	ENSP00000451460.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 61

GnomAD4 genome Cov.: 30

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	0.065
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.016	T
MetaRNN	Uncertain	0.44	T
MetaSVM	Benign	-0.64	T
MutationAssessor	Benign	1.6	L
PhyloP100		4.1
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.16
Sift	Benign	0.082	T
Sift4G	Benign	0.12	T
Polyphen		0.063	B
Vest4		0.56
MutPred		0.52		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;