chr6-30914859-C-A

Position:

chr6-30914859-C-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_020442.6(VARS2):c.23C>A(p.Ser8Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00027 in 1,612,952 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00031 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00027 ( 0 hom. )

Consequence

VARS2
NM_020442.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 0.827

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.059212416).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
VARS2	NM_020442.6 linkuse as main transcript	c.23C>A	p.Ser8Tyr	missense_variant	2/30	ENST00000676266.1
VARS2	NM_001167734.2 linkuse as main transcript	c.113C>A	p.Ser38Tyr	missense_variant	2/30
VARS2	NM_001167733.3 linkuse as main transcript	c.-219-297C>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VARS2	ENST00000676266.1 linkuse as main transcript	c.23C>A	p.Ser8Tyr	missense_variant	2/30		NM_020442.6	P3	Q5ST30-1

Frequencies

GnomAD3 genomes

AF:

0.000309

AC:

AN:

152188

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000523

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000456

Gnomad OTH

AF:

0.000957

GnomAD3 exomes

AF:

0.000223

AC:

AN:

246526

Hom.:

AF XY:

0.000260

AC XY:

AN XY:

134410

show subpopulations

Gnomad AFR exome

AF:

0.000133

Gnomad AMR exome

AF:

0.000348

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000334

Gnomad OTH exome

AF:

0.000659

GnomAD4 exome

AF:

0.000266

AC:

388

AN:

1460764

Hom.:

Cov.:

AF XY:

0.000267

AC XY:

194

AN XY:

726698

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.000268

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000326

Gnomad4 OTH exome

AF:

0.000182

GnomAD4 genome

AF:

0.000309

AC:

AN:

152188

Hom.:

Cov.:

AF XY:

0.000323

AC XY:

AN XY:

74342

show subpopulations

Gnomad4 AFR

AF:

0.000145

Gnomad4 AMR

AF:

0.000523

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000456

Gnomad4 OTH

AF:

0.000957

Alfa

AF:

0.000327

Hom.:

Bravo

AF:

0.000298

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000369

AC:

ExAC

AF:

0.000229

AC:

EpiCase

AF:

0.000218

EpiControl

AF:

0.000415

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Aug 09, 2022	This sequence change replaces serine, which is neutral and polar, with tyrosine, which is neutral and polar, at codon 38 of the VARS2 protein (p.Ser38Tyr). This variant is present in population databases (rs145694863, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with VARS2-related conditions. ClinVar contains an entry for this variant (Variation ID: 1300565). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Sep 28, 2021	Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant does not alter protein structure/function -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 27, 2021

The c.113C>A (p.S38Y) alteration is located in exon 2 (coding exon 2) of the VARS2 gene. This alteration results from a C to A substitution at nucleotide position 113, causing the serine (S) at amino acid position 38 to be replaced by a tyrosine (Y). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.41

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.0029

T;T;.;T

Eigen

Benign

-0.25

Eigen_PC

Benign

-0.34

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.71

T;T;T;T

M_CAP

Benign

0.0084

MetaRNN

Benign

0.059

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.2

M;.;.;.

MutationTaster

Benign

1.0

N;N;N;N

PrimateAI

Benign

0.40

PROVEAN

Benign

-0.30

N;N;N;N

REVEL

Benign

0.027

Sift

Uncertain

0.0010

D;D;D;D

Sift4G

Uncertain

0.023

D;D;D;D

Polyphen

0.68

P;.;.;.

Vest4

0.19

MVP

0.41

MPC

0.58

ClinPred

0.039

GERP RS

3.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.065

gMVP

0.25

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over