chr14-100337027-A-G

Variant names:

• chr14-100337027-A-G
• rs2234530
• NM_004184.4:c.1254+35T>C

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.1254+35T>C 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 1,597,568 control chromosomes in the GnomAD database, including 488,003 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.75 (43680 hom., cov: 32)
  • Exomes 𝑓: 0.78 (444323 hom.)
• Consequence: WARS1 NM_004184.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.00700
• Publications: 16 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=-0.86).
• BP6: Variant 14-100337027-A-G is Benign according to our data. Variant chr14-100337027-A-G is described in ClinVar as [Benign]. Clinvar id is 1252470.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.844 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WARS1	NM_004184.4	c.1254+35T>C		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.1254+35T>C		intron_variant	Intron 10 of 10	1	NM_004184.4	ENSP00000376620.2

Frequencies

GnomAD3 genomes AF: 0.753 AC: 114463 AN: 152026 Hom.: 43644 Cov.: 32

Gnomad AFR AF: 0.632

Gnomad AMI AF: 0.693

Gnomad AMR AF: 0.843

Gnomad ASJ AF: 0.843

Gnomad EAS AF: 0.865

Gnomad SAS AF: 0.838

Gnomad FIN AF: 0.812

Gnomad MID AF: 0.769

Gnomad NFE AF: 0.778

Gnomad OTH AF: 0.785

GnomAD2 exomes AF: 0.802 AC: 200767 AN: 250254 AF XY: 0.804

Gnomad AFR exome AF: 0.636

Gnomad AMR exome AF: 0.878

Gnomad ASJ exome AF: 0.835

Gnomad EAS exome AF: 0.864

Gnomad FIN exome AF: 0.814

Gnomad NFE exome AF: 0.779

Gnomad OTH exome AF: 0.807

GnomAD4 exome AF: 0.783 AC: 1131525 AN: 1445424 Hom.: 444323 Cov.: 46 AF XY: 0.785 AC XY: 561592 AN XY: 715672

African (AFR) AF: 0.625 AC: 20763 AN: 33218

American (AMR) AF: 0.872 AC: 38802 AN: 44502

Ashkenazi Jewish (ASJ) AF: 0.837 AC: 21642 AN: 25868

East Asian (EAS) AF: 0.879 AC: 34486 AN: 39252

South Asian (SAS) AF: 0.835 AC: 71778 AN: 85954

European-Finnish (FIN) AF: 0.816 AC: 43345 AN: 53128

Middle Eastern (MID) AF: 0.820 AC: 4687 AN: 5716

European-Non Finnish (NFE) AF: 0.773 AC: 849151 AN: 1098248

Other (OTH) AF: 0.787 AC: 46871 AN: 59538

GnomAD4 genome AF: 0.753 AC: 114551 AN: 152144 Hom.: 43680 Cov.: 32 AF XY: 0.758 AC XY: 56337 AN XY: 74366

African (AFR) AF: 0.632 AC: 26202 AN: 41484

American (AMR) AF: 0.844 AC: 12904 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.843 AC: 2927 AN: 3472

East Asian (EAS) AF: 0.866 AC: 4468 AN: 5162

South Asian (SAS) AF: 0.837 AC: 4039 AN: 4824

European-Finnish (FIN) AF: 0.812 AC: 8598 AN: 10592

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

European-Non Finnish (NFE) AF: 0.778 AC: 52892 AN: 67998

Other (OTH) AF: 0.786 AC: 1661 AN: 2112

Alfa AF: 0.775 Hom.: 14679

Bravo AF: 0.750

Asia WGS AF: 0.835 AC: 2906 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

May 16, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Neuronopathy, distal hereditary motor, type 9 Benign:1

Dec 05, 2021

Genome-Nilou Lab

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	-0.86
CADD	Benign	1.6
DANN	Benign	0.59
PhyloP100		-0.0070
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: rs2234530; hg19: chr14-100803364;