Genetic Variant NM_015836.4:c.*302A>G (chr1-119032609-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_015836.4(WARS2):c.*302A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.267 in 370,524 control chromosomes in the GnomAD database, including 14,563 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 0.29 ( 7256 hom., cov: 33)

Exomes 𝑓: 0.25 ( 7307 hom. )

Consequence

WARS2
NM_015836.4 3_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.202

Publications

14 publications found

Variant links:

Genes affected

WARS2 (HGNC:12730): (tryptophanyl tRNA synthetase 2, mitochondrial) 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. This gene encodes the mitochondrial tryptophanyl-tRNA synthetase. Two alternative transcripts encoding different isoforms have been described. [provided by RefSeq, Jul 2008]

WARS2 Gene-Disease associations (from GenCC):

mitochondrial disease
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
neurodevelopmental disorder, mitochondrial, with abnormal movements and lactic acidosis, with or without seizures
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

WARS2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.85).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.425 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WARS2	NM_015836.4 link	c.*302A>G		3_prime_UTR_variant	Exon 6 of 6	ENST00000235521.5	NP_056651.1	Q9UGM6-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WARS2	ENST00000235521.5 link	c.*302A>G		3_prime_UTR_variant	Exon 6 of 6	1	NM_015836.4	ENSP00000235521.4		Q9UGM6-1
WARS2	ENST00000369426.9 link	c.*751A>G		3_prime_UTR_variant	Exon 6 of 6	1		ENSP00000358434.5		Q9UGM6-2

Frequencies

GnomAD3 genomes

AF:

0.295

AC:

44805

AN:

151936

Hom.:

7248

Cov.:

show subpopulations

Gnomad AFR

AF:

0.430

Gnomad AMI

AF:

0.393

Gnomad AMR

AF:

0.191

Gnomad ASJ

AF:

0.225

Gnomad EAS

AF:

0.102

Gnomad SAS

AF:

0.263

Gnomad FIN

AF:

0.260

Gnomad MID

AF:

0.335

Gnomad NFE

AF:

0.261

Gnomad OTH

AF:

0.265

GnomAD4 exome

AF:

0.247

AC:

53913

AN:

218470

Hom.:

7307

Cov.:

AF XY:

0.246

AC XY:

27940

AN XY:

113698

show subpopulations

African (AFR)

AF:

0.420

AC:

2718

AN:

6472

American (AMR)

AF:

0.153

AC:

1112

AN:

7258

Ashkenazi Jewish (ASJ)

AF:

0.228

AC:

1571

AN:

6880

East Asian (EAS)

AF:

0.0901

AC:

1147

AN:

12726

South Asian (SAS)

AF:

0.255

AC:

5673

AN:

22284

European-Finnish (FIN)

AF:

0.253

AC:

3091

AN:

12216

Middle Eastern (MID)

AF:

0.262

AC:

260

AN:

994

European-Non Finnish (NFE)

AF:

0.256

AC:

35079

AN:

136804

Other (OTH)

AF:

0.254

AC:

3262

AN:

12836

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.511

Heterozygous variant carriers

1928

3856

5785

7713

9641

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

222

444

666

888

1110

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.295

AC:

44845

AN:

152054

Hom.:

7256

Cov.:

AF XY:

0.290

AC XY:

21526

AN XY:

74324

show subpopulations

African (AFR)

AF:

0.430

AC:

17830

AN:

41470

American (AMR)

AF:

0.190

AC:

2910

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.225

AC:

780

AN:

3470

East Asian (EAS)

AF:

0.102

AC:

529

AN:

5174

South Asian (SAS)

AF:

0.264

AC:

1272

AN:

4824

European-Finnish (FIN)

AF:

0.260

AC:

2749

AN:

10568

Middle Eastern (MID)

AF:

0.337

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.261

AC:

17763

AN:

67962

Other (OTH)

AF:

0.264

AC:

556

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1563

3126

4688

6251

7814

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

442

884

1326

1768

2210

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.264

Hom.:

7216

Bravo

AF:

0.292

Asia WGS

AF:

0.210

AC:

730

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.85

CADD

Benign

3.0

(source)

DANN

Benign

0.79

PhyloP100

-0.20

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over