6-30920091-G-T

Variant names:

• chr6-30920091-G-T
• rs202201763
• NM_020442.6:c.1168G>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PM5

The NM_001167734.2(VARS2):​c.1258G>T​(p.Ala420Ser) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000072 in 1,388,478 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. 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. A420T) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: VARS2 NM_001167734.2 missense, splice_region
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.79
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• mitochondrial disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• combined oxidative phosphorylation defect type 20

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ENSG00000288473 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr6-30920091-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 522814.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001167734.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VARS2	NM_020442.6	MANE Select	c.1168G>T	p.Ala390Ser	missense splice_region	Exon 13 of 30	NP_065175.4
	VARS2	NM_001167734.2		c.1258G>T	p.Ala420Ser	missense splice_region	Exon 13 of 30	NP_001161206.1
	VARS2	NM_001167733.3		c.748G>T	p.Ala250Ser	missense splice_region	Exon 12 of 29	NP_001161205.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VARS2	ENST00000676266.1	MANE Select	c.1168G>T	p.Ala390Ser	missense splice_region	Exon 13 of 30	ENSP00000502585.1
	VARS2	ENST00000321897.9	TSL:1	c.1168G>T	p.Ala390Ser	missense splice_region	Exon 12 of 29	ENSP00000316092.5
	VARS2	ENST00000476162.5	TSL:1	n.26G>T		splice_region non_coding_transcript_exon	Exon 2 of 18

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.20e-7 AC: 1 AN: 1388478 Hom.: 0 Cov.: 51 AF XY: 0.00 AC XY: 0 AN XY: 683432

African (AFR) AF: 0.00 AC: 0 AN: 31196

American (AMR) AF: 0.00 AC: 0 AN: 33546

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21312

East Asian (EAS) AF: 0.00 AC: 0 AN: 39108

South Asian (SAS) AF: 0.00 AC: 0 AN: 73386

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49898

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4948

European-Non Finnish (NFE) AF: 9.28e-7 AC: 1 AN: 1077824

Other (OTH) AF: 0.00 AC: 0 AN: 57260

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.16	T
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Benign	0.039	D
MetaRNN	Uncertain	0.67	D
MetaSVM	Benign	-0.44	T
MutationAssessor	Pathogenic	3.5	M
PhyloP100		8.8
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-2.6	D
REVEL	Uncertain	0.43
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.53
MutPred		0.70		Gain of glycosylation at A390 (P = 0.0128)
MVP		0.78
MPC		1.3
ClinPred		0.99	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.81
gMVP		0.85
Mutation Taster		=59/41	polymorphism

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

Other links and lift over

dbSNP: rs202201763; hg19: chr6-30887868;