NM_004184.4:c.1255-128C>G

Variant names:

• chr14-100335164-G-C
• rs45565635
• NM_004184.4:c.1255-128C>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_004184.4(WARS1):​c.1255-128C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0361 in 793,812 control chromosomes in the GnomAD database, including 709 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.039 (153 hom., cov: 32)
  • Exomes 𝑓: 0.035 (556 hom.)
• Consequence: WARS1 NM_004184.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.365
• 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: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 14-100335164-G-C is Benign according to our data. Variant chr14-100335164-G-C is described in ClinVar as [Benign]. Clinvar id is 1225395.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0725 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WARS1	NM_004184.4	c.1255-128C>G		intron_variant	Intron 10 of 10	ENST00000392882.7	NP_004175.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WARS1	ENST00000392882.7	c.1255-128C>G		intron_variant	Intron 10 of 10	1	NM_004184.4	ENSP00000376620.2

Frequencies

GnomAD3 genomes AF: 0.0388 AC: 5898 AN: 152128 Hom.: 153 Cov.: 32

Gnomad AFR AF: 0.0516

Gnomad AMI AF: 0.0833

Gnomad AMR AF: 0.0236

Gnomad ASJ AF: 0.0260

Gnomad EAS AF: 0.0786

Gnomad SAS AF: 0.0261

Gnomad FIN AF: 0.0285

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0342

Gnomad OTH AF: 0.0301

GnomAD4 exome AF: 0.0354 AC: 22725 AN: 641566 Hom.: 556 AF XY: 0.0351 AC XY: 11584 AN XY: 329972

African (AFR) AF: 0.0504 AC: 818 AN: 16218

American (AMR) AF: 0.0174 AC: 357 AN: 20492

Ashkenazi Jewish (ASJ) AF: 0.0227 AC: 341 AN: 15042

East Asian (EAS) AF: 0.0998 AC: 3243 AN: 32502

South Asian (SAS) AF: 0.0270 AC: 1360 AN: 50296

European-Finnish (FIN) AF: 0.0291 AC: 965 AN: 33166

Middle Eastern (MID) AF: 0.0422 AC: 101 AN: 2392

European-Non Finnish (NFE) AF: 0.0329 AC: 14425 AN: 439084

Other (OTH) AF: 0.0344 AC: 1115 AN: 32374

GnomAD4 genome AF: 0.0388 AC: 5907 AN: 152246 Hom.: 153 Cov.: 32 AF XY: 0.0381 AC XY: 2833 AN XY: 74440

African (AFR) AF: 0.0517 AC: 2147 AN: 41530

American (AMR) AF: 0.0236 AC: 361 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0260 AC: 90 AN: 3468

East Asian (EAS) AF: 0.0788 AC: 408 AN: 5178

South Asian (SAS) AF: 0.0257 AC: 124 AN: 4818

European-Finnish (FIN) AF: 0.0285 AC: 302 AN: 10614

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.0342 AC: 2326 AN: 68018

Other (OTH) AF: 0.0298 AC: 63 AN: 2116

Alfa AF: 0.0399 Hom.: 17

Bravo AF: 0.0375

Asia WGS AF: 0.0420 AC: 144 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

May 17, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	4.1
DANN	Benign	0.54
PhyloP100		0.36
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs45565635; hg19: chr14-100801501;