14-100335026-C-T

Variant names:

• chr14-100335026-C-T
• rs763195088
• NM_004184.4:c.1265G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_004184.4(WARS1):​c.1265G>A​(p.Ser422Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,642 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 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. S422T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: WARS1 NM_004184.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.77
• Publications: 0 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.37225205).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WARS1	NM_004184.4	c.1265G>A	p.Ser422Asn	missense_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.1265G>A	p.Ser422Asn	missense_variant	Exon 11 of 11	1	NM_004184.4	ENSP00000376620.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461642 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 727126

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39688

South Asian (SAS) AF: 0.00 AC: 0 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53376

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111878

Other (OTH) AF: 0.00 AC: 0 AN: 60382

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.013	T
BayesDel_noAF	Benign	-0.26
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.38	T;.;T;.;T;.
Eigen	Uncertain	0.24
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.97	.;.;.;.;D;D
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.37	T;T;T;T;T;T
MetaSVM	Benign	-0.32	T
MutationAssessor	Pathogenic	3.0	M;.;M;.;M;.
PhyloP100		7.8
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-2.3	N;N;N;N;N;N
REVEL	Benign	0.26
Sift	Uncertain	0.029	D;D;D;D;D;D
Sift4G	Benign	0.083	T;T;T;T;T;T
Polyphen		0.031	B;.;B;.;B;.
Vest4		0.50
MutPred		0.41		Gain of catalytic residue at M425 (P = 0.0014);.;Gain of catalytic residue at M425 (P = 0.0014);.;Gain of catalytic residue at M425 (P = 0.0014);.;
MVP		0.70
MPC		0.47
ClinPred		0.95	D
GERP RS		5.2
Varity_R		0.77
gMVP		0.73
Mutation Taster		=48/52	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: rs763195088; hg19: chr14-100801363;