ENST00000321897.9:c.-101A>G

Variant names:

• chr6-30914736-A-G
• rs1264303
• ENST00000321897.9:c.-101A>G

Variant summary

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

The ENST00000321897.9(VARS2):​c.-101A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.329 in 1,393,526 control chromosomes in the GnomAD database, including 78,916 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.28 (6827 hom., cov: 32)
  • Exomes 𝑓: 0.33 (72089 hom.)
• Consequence: VARS2 ENST00000321897.9 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.26
• Publications: 42 publications found

Genes affected

VARS2 (HGNC:21642): (valyl-tRNA synthetase 2, mitochondrial) This gene encodes a mitochondrial aminoacyl-tRNA synthetase, which catalyzes the attachment of valine to tRNA(Val) for mitochondrial translation. Mutations in this gene cause combined oxidative phosphorylation deficiency-20, and are also associated with early-onset mitochondrial encephalopathies. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, Aug 2014]

VARS2 Gene-Disease associations (from GenCC):

• mitochondrial disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• combined oxidative phosphorylation defect type 20

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ENSG00000288473 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 6-30914736-A-G is Benign according to our data. Variant chr6-30914736-A-G is described in ClinVar as Benign. ClinVar VariationId is 1247754.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.358 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VARS2	NM_020442.6	c.-27-74A>G		intron_variant	Intron 1 of 29	ENST00000676266.1	NP_065175.4
VARS2	NM_001167734.2	c.59-69A>G		intron_variant	Intron 1 of 29		NP_001161206.1
VARS2	NM_001167733.3	c.-220+392A>G		intron_variant	Intron 1 of 28		NP_001161205.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VARS2	ENST00000676266.1	c.-27-74A>G		intron_variant	Intron 1 of 29		NM_020442.6	ENSP00000502585.1

Frequencies

GnomAD3 genomes AF: 0.280 AC: 42526 AN: 152000 Hom.: 6830 Cov.: 32

Gnomad AFR AF: 0.124

Gnomad AMI AF: 0.307

Gnomad AMR AF: 0.242

Gnomad ASJ AF: 0.401

Gnomad EAS AF: 0.253

Gnomad SAS AF: 0.264

Gnomad FIN AF: 0.392

Gnomad MID AF: 0.377

Gnomad NFE AF: 0.362

Gnomad OTH AF: 0.281

GnomAD4 exome AF: 0.335 AC: 415491 AN: 1241408 Hom.: 72089 Cov.: 17 AF XY: 0.334 AC XY: 205956 AN XY: 616452

African (AFR) AF: 0.114 AC: 3213 AN: 28130

American (AMR) AF: 0.221 AC: 6604 AN: 29914

Ashkenazi Jewish (ASJ) AF: 0.370 AC: 7835 AN: 21174

East Asian (EAS) AF: 0.235 AC: 8628 AN: 36672

South Asian (SAS) AF: 0.272 AC: 19506 AN: 71648

European-Finnish (FIN) AF: 0.379 AC: 16822 AN: 44424

Middle Eastern (MID) AF: 0.325 AC: 1697 AN: 5224

European-Non Finnish (NFE) AF: 0.352 AC: 335092 AN: 951978

Other (OTH) AF: 0.308 AC: 16094 AN: 52244

GnomAD4 genome AF: 0.280 AC: 42536 AN: 152118 Hom.: 6827 Cov.: 32 AF XY: 0.281 AC XY: 20863 AN XY: 74364

African (AFR) AF: 0.125 AC: 5170 AN: 41524

American (AMR) AF: 0.242 AC: 3703 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.401 AC: 1391 AN: 3468

East Asian (EAS) AF: 0.253 AC: 1304 AN: 5162

South Asian (SAS) AF: 0.263 AC: 1267 AN: 4826

European-Finnish (FIN) AF: 0.392 AC: 4147 AN: 10580

Middle Eastern (MID) AF: 0.378 AC: 111 AN: 294

European-Non Finnish (NFE) AF: 0.362 AC: 24576 AN: 67958

Other (OTH) AF: 0.279 AC: 588 AN: 2108

Alfa AF: 0.336 Hom.: 36990

Bravo AF: 0.263

Asia WGS AF: 0.207 AC: 724 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Jul 31, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 44% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy, Progressive Myoclonus Epilepsy and Abnormal Movements and Neurodegeneration with brain iron accumulation. Number of patients: 41. Only high quality variants are reported. -

not provided Benign:1

Jun 23, 2018

GeneDx

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	-0.91
CADD	Benign	0.035
DANN	Benign	0.62
PhyloP100		-2.3
PromoterAI		0.040	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1264303; hg19: chr6-30882513; COSMIC: COSV52560646; COSMIC: COSV52560646;