rs770003315

Variant names:

• chr14-100346802-T-C
• rs770003315
• NM_004184.4:c.770A>G

Your query was ambiguous. Multiple possible variants found:

• chr14-100346802-T-C
• chr14-100346802-T-A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP5

The NM_004184.4(WARS1):​c.770A>G​(p.His257Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: WARS1 NM_004184.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 7.99
• Publications: 7 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: Labcorp Genetics (formerly Invitae), Broad Center for Mendelian Genomics
• neurodevelopmental disorder with microcephaly and speech delay, with or without brain abnormalities

  Inheritance: AR Classification: LIMITED Submitted by: G2P

WARS1-AS1 (HGNC:58289):

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 14-100346802-T-C is Pathogenic according to our data. Variant chr14-100346802-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 441278.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WARS1	NM_004184.4	MANE Select	c.770A>G	p.His257Arg	missense	Exon 7 of 11	NP_004175.2
	WARS1	NM_173701.2		c.770A>G	p.His257Arg	missense	Exon 7 of 11	NP_776049.1	P23381-1
	WARS1	NM_213645.2		c.647A>G	p.His216Arg	missense	Exon 6 of 10	NP_998810.1	P23381-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WARS1	ENST00000392882.7	TSL:1 MANE Select	c.770A>G	p.His257Arg	missense	Exon 7 of 11	ENSP00000376620.2	P23381-1
	WARS1	ENST00000355338.6	TSL:1	c.770A>G	p.His257Arg	missense	Exon 7 of 11	ENSP00000347495.2	P23381-1
	WARS1	ENST00000557135.5	TSL:1	c.770A>G	p.His257Arg	missense	Exon 8 of 12	ENSP00000451460.1	P23381-1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
1	1	-	Neuronopathy, distal hereditary motor, type 9 (2)
1	-	-	See cases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Pathogenic	0.16	D
BayesDel_noAF	Uncertain	0.0
CADD	Benign	22
DANN	Benign	0.97
DEOGEN2	Benign	0.13	T
Eigen	Uncertain	0.23
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.016	T
MetaRNN	Uncertain	0.48	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.14	N
PhyloP100		8.0
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-0.33	N
REVEL	Benign	0.19
Sift	Benign	0.37	T
Sift4G	Benign	0.36	T
Polyphen		0.0020	B
Vest4		0.90
MutPred		0.50		Gain of MoRF binding (P = 0.0065)
MVP		0.85
MPC		0.64
ClinPred		0.74	D
GERP RS		5.6
PromoterAI		-0.0040	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.58
gMVP		0.85
Mutation Taster		=3/97	disease causing (ClinVar)

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: rs770003315; hg19: chr14-100813139;