6-30926164-G-T

Variant names:

• chr6-30926164-G-T
• NM_020442.6:c.3146G>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_020442.6(VARS2):​c.3146G>T​(p.Arg1049Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,768 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1049Q) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: VARS2 NM_020442.6 missense
• Clinical Significance: Not reported in ClinVar
• 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]

ENSG00000288473 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.11018309).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VARS2	NM_020442.6	c.3146G>T	p.Arg1049Leu	missense_variant	Exon 30 of 30	ENST00000676266.1	NP_065175.4
VARS2	NM_001167734.2	c.3236G>T	p.Arg1079Leu	missense_variant	Exon 30 of 30		NP_001161206.1
VARS2	NM_001167733.3	c.2726G>T	p.Arg909Leu	missense_variant	Exon 29 of 29		NP_001161205.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VARS2	ENST00000676266.1	c.3146G>T	p.Arg1049Leu	missense_variant	Exon 30 of 30		NM_020442.6	ENSP00000502585.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460768 Hom.: 0 Cov.: 36 AF XY: 0.00 AC XY: 0 AN XY: 726696

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	7.4
DANN	Uncertain	0.98
DEOGEN2	Benign	0.013	T;.;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.050	N
LIST_S2	Benign	0.85	D;D;D
M_CAP	Benign	0.0098	T
MetaRNN	Benign	0.11	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.0	M;.;.
PrimateAI	Benign	0.25	T
PROVEAN	Uncertain	-2.4	N;.;N
REVEL	Benign	0.062
Sift	Uncertain	0.022	D;.;D
Sift4G	Benign	0.12	T;T;T
Polyphen		0.0	B;.;.
Vest4		0.25
MutPred		0.37		Loss of MoRF binding (P = 0.0395);.;.;
MVP		0.18
MPC		0.76
ClinPred		0.56	D
GERP RS		-8.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.056
gMVP		0.17

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-30893941;