rs773636381

Variant names:

• chr14-100337068-G-A
• rs773636381
• NM_004184.4:c.1248C>T

Your query was ambiguous. Multiple possible variants found:

• chr14-100337068-G-A
• chr14-100337068-G-C

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_Moderate BP7

The NM_004184.4(WARS1):​c.1248C>T​(p.Ile416Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000753 in 1,461,502 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.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: WARS1 NM_004184.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.38
• 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: Likely_benign. The variant received -3 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.39).
• BP7: Synonymous conserved (PhyloP=1.38 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WARS1	NM_004184.4	c.1248C>T	p.Ile416Ile	synonymous_variant	Exon 10 of 11	ENST00000392882.7	NP_004175.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WARS1	ENST00000392882.7	c.1248C>T	p.Ile416Ile	synonymous_variant	Exon 10 of 11	1	NM_004184.4	ENSP00000376620.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000239 AC: 6 AN: 251440 AF XY: 0.0000221

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000326

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000753 AC: 11 AN: 1461502 Hom.: 0 Cov.: 33 AF XY: 0.00000825 AC XY: 6 AN XY: 727012

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

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.000277 AC: 11 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86240

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53406

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111692

Other (OTH) AF: 0.00 AC: 0 AN: 60372

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.39
CADD	Benign	12
DANN	Benign	0.88
PhyloP100		1.4

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: rs773636381; hg19: chr14-100803405;