chr14-100337318-C-A

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004184.4(WARS1):​c.1114-116G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.78 in 1,489,466 control chromosomes in the GnomAD database, including 454,709 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.75 (43682 hom., cov: 32)
  • Exomes 𝑓: 0.78 (411027 hom.)
• Consequence: WARS1 NM_004184.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 14-100337318-C-A is Benign according to our data. Variant chr14-100337318-C-A is described in ClinVar as [Benign]. Clinvar id is 1267941.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.845 is higher than 0.05.

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes AF: 0.753 AC: 114452 AN: 152006 Hom.: 43646 Cov.: 32

Gnomad AFR AF: 0.632

Gnomad AMI AF: 0.689

Gnomad AMR AF: 0.843

Gnomad ASJ AF: 0.843

Gnomad EAS AF: 0.866

Gnomad SAS AF: 0.838

Gnomad FIN AF: 0.812

Gnomad MID AF: 0.769

Gnomad NFE AF: 0.778

Gnomad OTH AF: 0.784

GnomAD4 exome AF: 0.783 AC: 1046847 AN: 1337342 Hom.: 411027 AF XY: 0.785 AC XY: 516479 AN XY: 658318

African (AFR) AF: 0.626 AC: 19575 AN: 31288

American (AMR) AF: 0.872 AC: 35192 AN: 40348

Ashkenazi Jewish (ASJ) AF: 0.837 AC: 18385 AN: 21958

East Asian (EAS) AF: 0.879 AC: 33705 AN: 38334

South Asian (SAS) AF: 0.836 AC: 62371 AN: 74594

European-Finnish (FIN) AF: 0.816 AC: 32237 AN: 39526

Middle Eastern (MID) AF: 0.821 AC: 4356 AN: 5306

European-Non Finnish (NFE) AF: 0.774 AC: 797418 AN: 1030574

Other (OTH) AF: 0.787 AC: 43608 AN: 55414

GnomAD4 genome AF: 0.753 AC: 114540 AN: 152124 Hom.: 43682 Cov.: 32 AF XY: 0.758 AC XY: 56336 AN XY: 74356

African (AFR) AF: 0.632 AC: 26193 AN: 41466

American (AMR) AF: 0.844 AC: 12904 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.843 AC: 2926 AN: 3470

East Asian (EAS) AF: 0.866 AC: 4482 AN: 5176

South Asian (SAS) AF: 0.837 AC: 4032 AN: 4816

European-Finnish (FIN) AF: 0.812 AC: 8604 AN: 10596

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

European-Non Finnish (NFE) AF: 0.778 AC: 52879 AN: 67988

Other (OTH) AF: 0.786 AC: 1662 AN: 2114

Alfa AF: 0.692 Hom.: 2318

Bravo AF: 0.750

Asia WGS AF: 0.835 AC: 2906 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

May 16, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.14
DANN	Benign	0.54
PhyloP100		-1.3
Mutation Taster		=100/0	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: rs2234528; hg19: chr14-100803655;