rs4678

Positions:

• chr6-30926164-G-A

Variant summary

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

The NM_020442.6(VARS2):​c.3146G>A​(p.Arg1049Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.184 in 1,612,978 control chromosomes in the GnomAD database, including 29,832 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.15 (1916 hom., cov: 33)
  • Exomes 𝑓: 0.19 (27916 hom.)
• Consequence: VARS2 NM_020442.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.972

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0012257993).
• BP6: Variant 6-30926164-G-A is Benign according to our data. Variant chr6-30926164-G-A is described in ClinVar as [Benign]. Clinvar id is 380164.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.196 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VARS2	NM_020442.6	c.3146G>A	p.Arg1049Gln	missense_variant	30/30	ENST00000676266.1	NP_065175.4
VARS2	NM_001167734.2	c.3236G>A	p.Arg1079Gln	missense_variant	30/30		NP_001161206.1
VARS2	NM_001167733.3	c.2726G>A	p.Arg909Gln	missense_variant	29/29		NP_001161205.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VARS2	ENST00000676266.1	c.3146G>A	p.Arg1049Gln	missense_variant	30/30		NM_020442.6	ENSP00000502585.1

Frequencies

GnomAD3 genomes AF: 0.149 AC: 22729 AN: 152104 Hom.: 1912 Cov.: 33

Gnomad AFR AF: 0.119

Gnomad AMI AF: 0.230

Gnomad AMR AF: 0.0756

Gnomad ASJ AF: 0.143

Gnomad EAS AF: 0.0341

Gnomad SAS AF: 0.108

Gnomad FIN AF: 0.136

Gnomad MID AF: 0.0886

Gnomad NFE AF: 0.199

Gnomad OTH AF: 0.126

GnomAD3 exomes AF: 0.144 AC: 35496 AN: 246544 Hom.: 3045 AF XY: 0.148 AC XY: 19856 AN XY: 134404

Gnomad AFR exome AF: 0.124

Gnomad AMR exome AF: 0.0624

Gnomad ASJ exome AF: 0.156

Gnomad EAS exome AF: 0.0342

Gnomad SAS exome AF: 0.133

Gnomad FIN exome AF: 0.131

Gnomad NFE exome AF: 0.195

Gnomad OTH exome AF: 0.142

GnomAD4 exome AF: 0.188 AC: 274406 AN: 1460756 Hom.: 27916 Cov.: 36 AF XY: 0.187 AC XY: 135802 AN XY: 726692

Gnomad4 AFR exome AF: 0.122

Gnomad4 AMR exome AF: 0.0647

Gnomad4 ASJ exome AF: 0.156

Gnomad4 EAS exome AF: 0.0229

Gnomad4 SAS exome AF: 0.128

Gnomad4 FIN exome AF: 0.133

Gnomad4 NFE exome AF: 0.210

Gnomad4 OTH exome AF: 0.170

GnomAD4 genome AF: 0.150 AC: 22764 AN: 152222 Hom.: 1916 Cov.: 33 AF XY: 0.143 AC XY: 10640 AN XY: 74420

Gnomad4 AFR AF: 0.119

Gnomad4 AMR AF: 0.0753

Gnomad4 ASJ AF: 0.143

Gnomad4 EAS AF: 0.0341

Gnomad4 SAS AF: 0.109

Gnomad4 FIN AF: 0.136

Gnomad4 NFE AF: 0.199

Gnomad4 OTH AF: 0.125

Alfa AF: 0.185 Hom.: 5610

Bravo AF: 0.145

TwinsUK AF: 0.230 AC: 851

ALSPAC AF: 0.217 AC: 836

ESP6500AA AF: 0.122 AC: 367

ESP6500EA AF: 0.193 AC: 1047

ExAC AF: 0.145 AC: 17106

Asia WGS AF: 0.0810 AC: 282 AN: 3478

EpiCase AF: 0.196

EpiControl AF: 0.187

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 22, 2016	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Dec 04, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.76	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	0.38
DANN	Benign	0.62
DEOGEN2	Benign	0.00072	T;.;.
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.018	N
LIST_S2	Benign	0.74	T;T;T
MetaRNN	Benign	0.0012	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.11	N;.;.
PrimateAI	Benign	0.23	T
PROVEAN	Benign	0.43	N;.;N
REVEL	Benign	0.029
Sift	Benign	1.0	T;.;T
Sift4G	Benign	0.55	T;T;T
Polyphen		0.0	B;.;.
Vest4		0.037
MPC		0.52
ClinPred		0.00030	T
GERP RS		-8.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.020
gMVP		0.045

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

LitVar

Other links and lift over

dbSNP: rs4678; hg19: chr6-30893941;