rs61746524

chr6-30921099-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_020442.6(VARS2):c.1514C>T(p.Ser505Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00235 in 1,613,870 control chromosomes in the GnomAD database, including 96 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (52 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (44 hom.)
• Consequence: VARS2 NM_020442.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.19

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 (MetaRNN=0.0051003397).
• BP6: Variant 6-30921099-C-T is Benign according to our data. Variant chr6-30921099-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 381460.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0129 (1965/152266) while in subpopulation AFR AF= 0.0449 (1866/41524). AF 95% confidence interval is 0.0432. There are 52 homozygotes in gnomad4. There are 859 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 52 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VARS2	NM_020442.6	c.1514C>T	p.Ser505Phe	missense_variant	16/30	ENST00000676266.1
VARS2	NM_001167734.2	c.1604C>T	p.Ser535Phe	missense_variant	16/30
VARS2	NM_001167733.3	c.1094C>T	p.Ser365Phe	missense_variant	15/29

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VARS2	ENST00000676266.1	c.1514C>T	p.Ser505Phe	missense_variant	16/30		NM_020442.6	P3

Frequencies

GnomAD3 genomes AF: 0.0129 AC: 1961 AN: 152148 Hom.: 52 Cov.: 32

Gnomad AFR AF: 0.0450

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00432

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: 0.000235

Gnomad OTH AF: 0.00813

GnomAD3 exomes AF: 0.00329 AC: 827 AN: 251056 Hom.: 16 AF XY: 0.00226 AC XY: 307 AN XY: 135702

Gnomad AFR exome AF: 0.0440

Gnomad AMR exome AF: 0.00246

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000185

Gnomad OTH exome AF: 0.000980

GnomAD4 exome AF: 0.00125 AC: 1823 AN: 1461604 Hom.: 44 Cov.: 33 AF XY: 0.00100 AC XY: 727 AN XY: 727104

Gnomad4 AFR exome AF: 0.0424

Gnomad4 AMR exome AF: 0.00295

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000863

Gnomad4 OTH exome AF: 0.00267

GnomAD4 genome AF: 0.0129 AC: 1965 AN: 152266 Hom.: 52 Cov.: 32 AF XY: 0.0115 AC XY: 859 AN XY: 74438

Gnomad4 AFR AF: 0.0449

Gnomad4 AMR AF: 0.00431

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000235

Gnomad4 OTH AF: 0.00805

Alfa AF: 0.00459 Hom.: 6

Bravo AF: 0.0147

ESP6500AA AF: 0.0399 AC: 176

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00395 AC: 480

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000356

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Apr 19, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 18, 2023	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 15, 2016

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	0.11
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.43
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Benign	0.041	T;.;.
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.54	T;T;T
MetaRNN	Benign	0.0051	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.1	M;.;.
MutationTaster	Benign	0.96	N;N;N;N
PrimateAI	Benign	0.39	T
PROVEAN	Uncertain	-3.3	D;.;D
REVEL	Benign	0.096
Sift	Uncertain	0.0090	D;.;D
Sift4G	Uncertain	0.028	D;D;D
Polyphen		0.91	P;.;.
Vest4		0.34
MVP		0.62
MPC		0.88
ClinPred		0.027	T
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.14
gMVP		0.49

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: rs61746524; hg19: chr6-30888876;