chr14-100335086-T-C

Variant names:

• chr14-100335086-T-C
• rs2234532
• NM_004184.4:c.1255-50A>G

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.1255-50A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.992 in 1,591,454 control chromosomes in the GnomAD database, including 784,281 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.96 (70827 hom., cov: 32)
  • Exomes 𝑓: 1.0 (713454 hom.)
• Consequence: WARS1 NM_004184.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.46
• Publications: 2 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=-0.92).
• BP6: Variant 14-100335086-T-C is Benign according to our data. Variant chr14-100335086-T-C is described in ClinVar as [Benign]. Clinvar id is 1251090.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.993 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WARS1	NM_004184.4	c.1255-50A>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.1255-50A>G		intron_variant	Intron 10 of 10	1	NM_004184.4	ENSP00000376620.2

Frequencies

GnomAD3 genomes AF: 0.963 AC: 146502 AN: 152148 Hom.: 70776 Cov.: 32

Gnomad AFR AF: 0.875

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.979

Gnomad ASJ AF: 0.993

Gnomad EAS AF: 0.999

Gnomad SAS AF: 0.999

Gnomad FIN AF: 1.00

Gnomad MID AF: 0.972

Gnomad NFE AF: 0.999

Gnomad OTH AF: 0.973

GnomAD2 exomes AF: 0.989 AC: 235284 AN: 237862 AF XY: 0.992

Gnomad AFR exome AF: 0.874

Gnomad AMR exome AF: 0.992

Gnomad ASJ exome AF: 0.993

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 1.00

Gnomad NFE exome AF: 0.999

Gnomad OTH exome AF: 0.991

GnomAD4 exome AF: 0.996 AC: 1432734 AN: 1439188 Hom.: 713454 Cov.: 28 AF XY: 0.996 AC XY: 710438 AN XY: 713350

African (AFR) AF: 0.871 AC: 28827 AN: 33094

American (AMR) AF: 0.991 AC: 43186 AN: 43580

Ashkenazi Jewish (ASJ) AF: 0.993 AC: 25102 AN: 25272

East Asian (EAS) AF: 0.999 AC: 39284 AN: 39316

South Asian (SAS) AF: 0.998 AC: 84264 AN: 84410

European-Finnish (FIN) AF: 1.00 AC: 50922 AN: 50924

Middle Eastern (MID) AF: 0.985 AC: 5289 AN: 5368

European-Non Finnish (NFE) AF: 0.999 AC: 1097034 AN: 1097794

Other (OTH) AF: 0.990 AC: 58826 AN: 59430

GnomAD4 genome AF: 0.963 AC: 146611 AN: 152266 Hom.: 70827 Cov.: 32 AF XY: 0.964 AC XY: 71765 AN XY: 74450

African (AFR) AF: 0.876 AC: 36357 AN: 41526

American (AMR) AF: 0.979 AC: 14982 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.993 AC: 3448 AN: 3472

East Asian (EAS) AF: 0.999 AC: 5159 AN: 5164

South Asian (SAS) AF: 0.999 AC: 4822 AN: 4826

European-Finnish (FIN) AF: 1.00 AC: 10624 AN: 10624

Middle Eastern (MID) AF: 0.969 AC: 285 AN: 294

European-Non Finnish (NFE) AF: 0.999 AC: 67966 AN: 68034

Other (OTH) AF: 0.973 AC: 2056 AN: 2112

Alfa AF: 0.971 Hom.: 19321

Bravo AF: 0.958

Asia WGS AF: 0.991 AC: 3446 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	-0.92
CADD	Benign	1.5
DANN	Benign	0.34
PhyloP100		-1.5
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: rs2234532; hg19: chr14-100801423;