6-30914809-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PVS1_Moderate PM2

The NM_020442.6(VARS2):c.-27-1G>T variant causes a splice acceptor change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000157 in 1,460,542 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: VARS2 NM_020442.6 splice_acceptor
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 1.89

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 Uncertain_significance. Variant got 4 ACMG points.

• PVS1: Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 0.011852548 fraction of the gene. Cryptic splice site detected, with MaxEntScore 12, offset of -5, new splice context is: tgtgctctctctctatccAGaac. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VARS2	NM_020442.6	c.-27-1G>T		splice_acceptor_variant		ENST00000676266.1
VARS2	NM_001167734.2	c.63G>T	p.Gln21His	missense_variant	2/30
VARS2	NM_001167733.3	c.-219-347G>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VARS2	ENST00000676266.1	c.-27-1G>T		splice_acceptor_variant			NM_020442.6	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000407 AC: 1 AN: 245720 Hom.: 0 AF XY: 0.00000745 AC XY: 1 AN XY: 134176

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.00000906

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000157 AC: 23 AN: 1460542 Hom.: 0 Cov.: 31 AF XY: 0.0000151 AC XY: 11 AN XY: 726588

Gnomad4 AFR exome AF: 0.0000299

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: 0.0000198

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

Mar 11, 2016

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
Cadd	Benign	22
Dann	Benign	0.90
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.30
FATHMM_MKL	Benign	0.38	N
LIST_S2	Benign	0.40	T
M_CAP	Benign	0.0072	T
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-0.93	T
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-0.34	N
REVEL	Benign	0.049
Sift	Uncertain	0.017	D
Sift4G	Pathogenic	0.0	D
Vest4		0.28
MutPred		0.18		Loss of helix (P = 0.1706);
MVP		0.28
MPC		0.69
ClinPred		0.18	T
GERP RS		2.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
gMVP		0.27

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1212840317; hg19: chr6-30882586;