6-30914426-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000321897.9(VARS2):c.-411T>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.543 in 1,271,196 control chromosomes in the GnomAD database, including 191,105 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.54 (23273 hom., cov: 33)
  • Exomes 𝑓: 0.54 (167832 hom.)
• Consequence: VARS2 ENST00000321897.9 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.54

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 6-30914426-T-C is Benign according to our data. Variant chr6-30914426-T-C is described in ClinVar as [Benign]. Clinvar id is 380148.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.84 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VARS2	NM_020442.6	c.-28+82T>C		intron_variant		ENST00000676266.1
VARS2	NM_001167734.2	c.15T>C	p.Ala5=	synonymous_variant	1/30
VARS2	NM_001167733.3	c.-220+82T>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VARS2	ENST00000676266.1	c.-28+82T>C		intron_variant			NM_020442.6	P3

Frequencies

GnomAD3 genomes AF: 0.540 AC: 82139 AN: 152052 Hom.: 23260 Cov.: 33

Gnomad AFR AF: 0.396

Gnomad AMI AF: 0.608

Gnomad AMR AF: 0.610

Gnomad ASJ AF: 0.657

Gnomad EAS AF: 0.861

Gnomad SAS AF: 0.774

Gnomad FIN AF: 0.650

Gnomad MID AF: 0.599

Gnomad NFE AF: 0.547

Gnomad OTH AF: 0.536

GnomAD3 exomes AF: 0.550 AC: 1768 AN: 3216 Hom.: 519 AF XY: 0.556 AC XY: 856 AN XY: 1540

Gnomad AFR exome AF: 0.308

Gnomad AMR exome AF: 0.621

Gnomad ASJ exome AF: 0.531

Gnomad EAS exome AF: 0.854

Gnomad SAS exome AF: 0.637

Gnomad FIN exome AF: 0.643

Gnomad NFE exome AF: 0.514

Gnomad OTH exome AF: 0.509

GnomAD4 exome AF: 0.543 AC: 607468 AN: 1119026 Hom.: 167832 Cov.: 56 AF XY: 0.544 AC XY: 289351 AN XY: 531902

Gnomad4 AFR exome AF: 0.368

Gnomad4 AMR exome AF: 0.639

Gnomad4 ASJ exome AF: 0.636

Gnomad4 EAS exome AF: 0.801

Gnomad4 SAS exome AF: 0.741

Gnomad4 FIN exome AF: 0.646

Gnomad4 NFE exome AF: 0.528

Gnomad4 OTH exome AF: 0.562

GnomAD4 genome AF: 0.540 AC: 82186 AN: 152170 Hom.: 23273 Cov.: 33 AF XY: 0.552 AC XY: 41037 AN XY: 74384

Gnomad4 AFR AF: 0.396

Gnomad4 AMR AF: 0.610

Gnomad4 ASJ AF: 0.657

Gnomad4 EAS AF: 0.861

Gnomad4 SAS AF: 0.772

Gnomad4 FIN AF: 0.650

Gnomad4 NFE AF: 0.547

Gnomad4 OTH AF: 0.541

Alfa AF: 0.530 Hom.: 2725

Bravo AF: 0.529

Asia WGS AF: 0.759 AC: 2641 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 19, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Dec 22, 2015

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Combined oxidative phosphorylation defect type 20 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Dec 05, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
Cadd	Benign	5.2
Dann	Benign	0.73
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1264306; hg19: chr6-30882203;