chr14-100337318-C-T

Variant names:

• chr14-100337318-C-T
• rs2234528
• NM_004184.4:c.1114-116G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_004184.4(WARS1):​c.1114-116G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000149 in 1,339,226 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: 32)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: WARS1 NM_004184.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.32
• Publications: 8 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 -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WARS1	NM_004184.4	c.1114-116G>A		intron_variant	Intron 9 of 10	ENST00000392882.7	NP_004175.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WARS1	ENST00000392882.7	c.1114-116G>A		intron_variant	Intron 9 of 10	1	NM_004184.4	ENSP00000376620.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000149 AC: 2 AN: 1339226 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 659166

⚠️ 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: 31322

American (AMR) AF: 0.0000248 AC: 1 AN: 40376

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21974

East Asian (EAS) AF: 0.00 AC: 0 AN: 38360

South Asian (SAS) AF: 0.00 AC: 0 AN: 74696

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39566

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5312

European-Non Finnish (NFE) AF: 9.69e-7 AC: 1 AN: 1032142

Other (OTH) AF: 0.00 AC: 0 AN: 55478

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000203), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 2318

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.40
DANN	Benign	0.90
PhyloP100		-1.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs2234528; hg19: chr14-100803655;