6-31779044-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 1P and 14B. PP2 BP4_Strong BP6_Moderate BS1 BS2

The NM_006295.3(VARS1):c.3649C>T(p.Arg1217Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000843 in 1,612,510 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1217H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00073 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00086 (17 hom.)
• Consequence: VARS1 NM_006295.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.24

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 Benign. Variant got -13 ACMG points.

• PP2: Missense variant where missense usually causes diseases, VARS1
• BP4: Computational evidence support a benign effect (MetaRNN=0.008346707).
• BP6: Variant 6-31779044-G-A is Benign according to our data. Variant chr6-31779044-G-A is described in ClinVar as [Benign]. Clinvar id is 3045730.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000729 (111/152340) while in subpopulation EAS AF= 0.0202 (105/5188). AF 95% confidence interval is 0.0171. There are 1 homozygotes in gnomad4. There are 56 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VARS1	NM_006295.3	c.3649C>T	p.Arg1217Cys	missense_variant	29/30	ENST00000375663.8
VARS1	XM_005249362.3	c.3652C>T	p.Arg1218Cys	missense_variant	29/30
VARS1	XM_047419296.1	c.3652C>T	p.Arg1218Cys	missense_variant	28/29
VARS1	XM_047419297.1	c.3649C>T	p.Arg1217Cys	missense_variant	28/29

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VARS1	ENST00000375663.8	c.3649C>T	p.Arg1217Cys	missense_variant	29/30	1	NM_006295.3	P1

Frequencies

GnomAD3 genomes AF: 0.000736 AC: 112 AN: 152222 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0204

Gnomad SAS AF: 0.000620

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00224 AC: 542 AN: 242426 Hom.: 5 AF XY: 0.00213 AC XY: 283 AN XY: 132950

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0287

Gnomad SAS exome AF: 0.000626

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000185

Gnomad OTH exome AF: 0.00101

GnomAD4 exome AF: 0.000855 AC: 1249 AN: 1460170 Hom.: 17 Cov.: 32 AF XY: 0.000859 AC XY: 624 AN XY: 726416

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0281

Gnomad4 SAS exome AF: 0.000904

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000135

Gnomad4 OTH exome AF: 0.000614

GnomAD4 genome AF: 0.000729 AC: 111 AN: 152340 Hom.: 1 Cov.: 33 AF XY: 0.000752 AC XY: 56 AN XY: 74496

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0202

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000994 Hom.: 6

Bravo AF: 0.000963

ExAC AF: 0.00214 AC: 251

Asia WGS AF: 0.00520 AC: 19 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

VARS1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 13, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.41
Cadd	Pathogenic	33
Dann	Uncertain	1.0
DEOGEN2	Benign	0.35	T
Eigen	Uncertain	0.24
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.95	D
MetaRNN	Benign	0.0083	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	2.0	M
MutationTaster	Benign	0.99	D
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-3.9	D
REVEL	Benign	0.13
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0060	D
Polyphen		1.0	D
Vest4		0.50
MVP		0.33
MPC		1.3
ClinPred		0.073	T
GERP RS		3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.24
gMVP		0.52

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: rs181542871; hg19: chr6-31746821; COSMIC: COSV63304804; COSMIC: COSV63304804;