chr14-100374259-G-C

Variant names:

• chr14-100374259-G-C
• rs941928
• ENST00000557135.5:c.-197C>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000557135.5(WARS1):​c.-197C>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.75 in 152,160 control chromosomes in the GnomAD database, including 43,402 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 0.75 (43401 hom., cov: 33)
  • Exomes 𝑓: 1.0 (1 hom.)
• Consequence: WARS1 ENST00000557135.5 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0990
• Publications: 14 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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.844 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000557135.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WARS1	NM_004184.4	MANE Select	c.-74+1024C>G		intron	N/A	NP_004175.2
	WARS1	NM_173701.2		c.-74+2001C>G		intron	N/A	NP_776049.1
	WARS1	NM_213645.2		c.-25+2001C>G		intron	N/A	NP_998810.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WARS1	ENST00000557135.5	TSL:1	c.-197C>G		5_prime_UTR	Exon 2 of 12	ENSP00000451460.1
	WARS1	ENST00000392882.7	TSL:1 MANE Select	c.-74+1024C>G		intron	N/A	ENSP00000376620.2
	WARS1	ENST00000355338.6	TSL:1	c.-74+2001C>G		intron	N/A	ENSP00000347495.2

Frequencies

GnomAD3 genomes AF: 0.750 AC: 114020 AN: 152040 Hom.: 43370 Cov.: 33

Gnomad AFR AF: 0.621

Gnomad AMI AF: 0.693

Gnomad AMR AF: 0.843

Gnomad ASJ AF: 0.841

Gnomad EAS AF: 0.865

Gnomad SAS AF: 0.838

Gnomad FIN AF: 0.812

Gnomad MID AF: 0.769

Gnomad NFE AF: 0.777

Gnomad OTH AF: 0.781

GnomAD4 exome AF: 1.00 AC: 2 AN: 2 Hom.: 1 Cov.: 0 AF XY: 1.00 AC XY: 2 AN XY: 2

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AF: 1.00 AC: 2 AN: 2

European-Non Finnish (NFE) AC: 0 AN: 0

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.750 AC: 114103 AN: 152158 Hom.: 43401 Cov.: 33 AF XY: 0.755 AC XY: 56149 AN XY: 74382

African (AFR) AF: 0.621 AC: 25771 AN: 41474

American (AMR) AF: 0.844 AC: 12899 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.841 AC: 2921 AN: 3472

East Asian (EAS) AF: 0.866 AC: 4484 AN: 5180

South Asian (SAS) AF: 0.837 AC: 4042 AN: 4828

European-Finnish (FIN) AF: 0.812 AC: 8593 AN: 10586

Middle Eastern (MID) AF: 0.786 AC: 231 AN: 294

European-Non Finnish (NFE) AF: 0.777 AC: 52879 AN: 68014

Other (OTH) AF: 0.783 AC: 1654 AN: 2112

Alfa AF: 0.756 Hom.: 5442

Bravo AF: 0.747

Asia WGS AF: 0.834 AC: 2903 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	5.3
DANN	Benign	0.55
PhyloP100		-0.099
Mutation Taster		=300/0	polymorphism (auto)

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: rs941928; hg19: chr14-100840596;