14-100376300-C-G

Variant names:

• chr14-100376300-C-G
• rs2273804
• ENST00000355338.6:c.-114G>C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_173701.2(WARS1):​c.-114G>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.241 in 1,026,592 control chromosomes in the GnomAD database, including 31,279 homozygotes. 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: 𝑓 0.19 (3255 hom., cov: 33)
  • Exomes 𝑓: 0.25 (28024 hom.)
• Consequence: WARS1 NM_173701.2 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.17

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]

WDR25 (HGNC:21064): (WD repeat domain 25) This gene encodes a protein containing 7 WD repeats. WD repeats are approximately 30 to 40-amino acid domains containing several conserved residues, typically having a Tryptophan-Aspartic acid dipeptide (WD) at the C-terminal end. WD domains are involved in protein-protein interactions in a variety of cellular processes, including cell cycle progression, signal transduction, apoptosis, and gene regulation. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Apr 2017]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.252 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WDR25	NM_001161476.3	c.-211C>G		upstream_gene_variant		ENST00000402312.8	NP_001154948.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WDR25	ENST00000402312.8	c.-211C>G		upstream_gene_variant		2	NM_001161476.3	ENSP00000385540.3

Frequencies

GnomAD3 genomes AF: 0.194 AC: 29568 AN: 152192 Hom.: 3257 Cov.: 33

Gnomad AFR AF: 0.105

Gnomad AMI AF: 0.393

Gnomad AMR AF: 0.141

Gnomad ASJ AF: 0.177

Gnomad EAS AF: 0.212

Gnomad SAS AF: 0.185

Gnomad FIN AF: 0.217

Gnomad MID AF: 0.218

Gnomad NFE AF: 0.255

Gnomad OTH AF: 0.182

GnomAD4 exome AF: 0.249 AC: 217783 AN: 874282 Hom.: 28024 Cov.: 12 AF XY: 0.249 AC XY: 103964 AN XY: 417168

Gnomad4 AFR exome AF: 0.0935

Gnomad4 AMR exome AF: 0.140

Gnomad4 ASJ exome AF: 0.180

Gnomad4 EAS exome AF: 0.221

Gnomad4 SAS exome AF: 0.193

Gnomad4 FIN exome AF: 0.211

Gnomad4 NFE exome AF: 0.260

Gnomad4 OTH exome AF: 0.223

GnomAD4 genome AF: 0.194 AC: 29561 AN: 152310 Hom.: 3255 Cov.: 33 AF XY: 0.192 AC XY: 14288 AN XY: 74480

Gnomad4 AFR AF: 0.105

Gnomad4 AMR AF: 0.140

Gnomad4 ASJ AF: 0.177

Gnomad4 EAS AF: 0.212

Gnomad4 SAS AF: 0.186

Gnomad4 FIN AF: 0.217

Gnomad4 NFE AF: 0.255

Gnomad4 OTH AF: 0.181

Alfa AF: 0.137 Hom.: 260

Bravo AF: 0.184

Asia WGS AF: 0.182 AC: 630 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	0.18
DANN	Benign	0.51

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs2273804; hg19: chr14-100842637;