chr1-119032674-C-G

Variant names:

• chr1-119032674-C-G
• rs3790548
• NM_015836.4:c.*237G>C

Variant summary

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

The NM_015836.4(WARS2):​c.*237G>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0578 in 517,860 control chromosomes in the GnomAD database, including 1,302 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.066 (458 hom., cov: 33)
  • Exomes 𝑓: 0.054 (844 hom.)
• Consequence: WARS2 NM_015836.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.69
• Publications: 2 publications found

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)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 1-119032674-C-G is Benign according to our data. Variant chr1-119032674-C-G is described in ClinVar as Benign. ClinVar VariationId is 1251531.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.186 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015836.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WARS2	NM_015836.4	MANE Select	c.*237G>C		3_prime_UTR	Exon 6 of 6	NP_056651.1	Q9UGM6-1
	WARS2	NM_001378226.1		c.*237G>C		3_prime_UTR	Exon 7 of 7	NP_001365155.1
	WARS2	NM_001378227.1		c.*237G>C		3_prime_UTR	Exon 8 of 8	NP_001365156.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WARS2	ENST00000235521.5	TSL:1 MANE Select	c.*237G>C		3_prime_UTR	Exon 6 of 6	ENSP00000235521.4	Q9UGM6-1
	WARS2	ENST00000369426.9	TSL:1	c.*686G>C		3_prime_UTR	Exon 6 of 6	ENSP00000358434.5	Q9UGM6-2
	WARS2	ENST00000928547.1		c.*237G>C		3_prime_UTR	Exon 7 of 7	ENSP00000598606.1

Frequencies

GnomAD3 genomes AF: 0.0664 AC: 10102 AN: 152138 Hom.: 452 Cov.: 33

Gnomad AFR AF: 0.103

Gnomad AMI AF: 0.0537

Gnomad AMR AF: 0.0531

Gnomad ASJ AF: 0.0395

Gnomad EAS AF: 0.197

Gnomad SAS AF: 0.0609

Gnomad FIN AF: 0.0303

Gnomad MID AF: 0.0601

Gnomad NFE AF: 0.0447

Gnomad OTH AF: 0.0636

GnomAD4 exome AF: 0.0542 AC: 19810 AN: 365604 Hom.: 844 Cov.: 4 AF XY: 0.0539 AC XY: 10285 AN XY: 190870

African (AFR) AF: 0.0981 AC: 1024 AN: 10436

American (AMR) AF: 0.0396 AC: 467 AN: 11802

Ashkenazi Jewish (ASJ) AF: 0.0356 AC: 412 AN: 11578

East Asian (EAS) AF: 0.173 AC: 4288 AN: 24824

South Asian (SAS) AF: 0.0542 AC: 1769 AN: 32640

European-Finnish (FIN) AF: 0.0337 AC: 800 AN: 23746

Middle Eastern (MID) AF: 0.0402 AC: 67 AN: 1666

European-Non Finnish (NFE) AF: 0.0430 AC: 9767 AN: 227300

Other (OTH) AF: 0.0563 AC: 1216 AN: 21612

GnomAD4 genome AF: 0.0665 AC: 10119 AN: 152256 Hom.: 458 Cov.: 33 AF XY: 0.0653 AC XY: 4858 AN XY: 74436

African (AFR) AF: 0.103 AC: 4282 AN: 41522

American (AMR) AF: 0.0531 AC: 812 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0395 AC: 137 AN: 3470

East Asian (EAS) AF: 0.196 AC: 1017 AN: 5178

South Asian (SAS) AF: 0.0607 AC: 293 AN: 4826

European-Finnish (FIN) AF: 0.0303 AC: 322 AN: 10616

Middle Eastern (MID) AF: 0.0612 AC: 18 AN: 294

European-Non Finnish (NFE) AF: 0.0446 AC: 3037 AN: 68024

Other (OTH) AF: 0.0719 AC: 152 AN: 2114

Alfa AF: 0.0213 Hom.: 13

Bravo AF: 0.0681

Asia WGS AF: 0.147 AC: 511 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.37
DANN	Benign	0.74
PhyloP100		-1.7
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: rs3790548; hg19: chr1-119575297;