6-31779439-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_006295.3(VARS1):c.3386G>A(p.Arg1129Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000362 in 1,612,084 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00030 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00037 (0 hom.)
• Consequence: VARS1 NM_006295.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.65

Genes affected

VARS1 (HGNC:12651): (valyl-tRNA synthetase 1) Aminoacyl-tRNA synthetases catalyze the aminoacylation of tRNA by their cognate amino acid. Because of their central role in linking amino acids with nucleotide triplets contained in tRNAs, aminoacyl-tRNA synthetases are thought to be among the first proteins that appeared in evolution. The protein encoded by this gene belongs to class-I aminoacyl-tRNA synthetase family and is located in the class III region of the major histocompatibility complex. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, VARS1
• BP4: Computational evidence support a benign effect (MetaRNN=0.086399406).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VARS1	NM_006295.3	c.3386G>A	p.Arg1129Gln	missense_variant	28/30	ENST00000375663.8
VARS1	XM_005249362.3	c.3389G>A	p.Arg1130Gln	missense_variant	28/30
VARS1	XM_047419296.1	c.3389G>A	p.Arg1130Gln	missense_variant	27/29
VARS1	XM_047419297.1	c.3386G>A	p.Arg1129Gln	missense_variant	27/29

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VARS1	ENST00000375663.8	c.3386G>A	p.Arg1129Gln	missense_variant	28/30	1	NM_006295.3	P1
VARS1	ENST00000463184.1	n.542G>A		non_coding_transcript_exon_variant	2/3	2

Frequencies

GnomAD3 genomes AF: 0.000296 AC: 45 AN: 152152 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000573

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000361 AC: 88 AN: 244036 Hom.: 0 AF XY: 0.000382 AC XY: 51 AN XY: 133576

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000262

Gnomad ASJ exome AF: 0.000101

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000677

Gnomad OTH exome AF: 0.000663

GnomAD4 exome AF: 0.000369 AC: 538 AN: 1459814 Hom.: 0 Cov.: 32 AF XY: 0.000347 AC XY: 252 AN XY: 726302

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000313

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.0000389

Gnomad4 NFE exome AF: 0.000455

Gnomad4 OTH exome AF: 0.000232

GnomAD4 genome AF: 0.000296 AC: 45 AN: 152270 Hom.: 0 Cov.: 32 AF XY: 0.000269 AC XY: 20 AN XY: 74448

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.000573

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000464 Hom.: 0

Bravo AF: 0.000408

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000370 AC: 2

ExAC AF: 0.000297 AC: 35

EpiCase AF: 0.000491

EpiControl AF: 0.000415

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 24, 2022

The c.3386G>A (p.R1129Q) alteration is located in exon 28 (coding exon 27) of the VARS gene. This alteration results from a G to A substitution at nucleotide position 3386, causing the arginine (R) at amino acid position 1129 to be replaced by a glutamine (Q). Based on data from the Genome Aggregation Database (gnomAD) database, the VARS c.3386G>A alteration was observed in 0.03% (94/275388) of total alleles studied, with a frequency of 0.06% (79/124722) in the European (non-Finnish) subpopulation. This amino acid position is well conserved in available vertebrate species. The p.R1129Q alteration is predicted to be tolerated by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Neurodevelopmental disorder with microcephaly, seizures, and cortical atrophy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Apr 03, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.54
Cadd	Pathogenic	27
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.0087	T
Eigen	Uncertain	0.26
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Benign	0.72	D
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.086	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.28	N
MutationTaster	Benign	0.86	N
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.074
Sift	Benign	0.034	D
Sift4G	Uncertain	0.040	D
Polyphen		0.98	D
Vest4		0.44
MVP		0.23
MPC		0.96
ClinPred		0.12	T
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.063
gMVP		0.36

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

Other links and lift over

dbSNP: rs150145769; hg19: chr6-31747216;