6-31779098-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP6_Moderate

The NM_006295.3(VARS1):c.3595C>T(p.Arg1199Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000245 in 1,611,012 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1199Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00025 (0 hom.)
• Consequence: VARS1 NM_006295.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.78

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
• BP6: Variant 6-31779098-G-A is Benign according to our data. Variant chr6-31779098-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 3188187.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VARS1	NM_006295.3	c.3595C>T	p.Arg1199Trp	missense_variant	29/30	ENST00000375663.8
VARS1	XM_005249362.3	c.3598C>T	p.Arg1200Trp	missense_variant	29/30
VARS1	XM_047419296.1	c.3598C>T	p.Arg1200Trp	missense_variant	28/29
VARS1	XM_047419297.1	c.3595C>T	p.Arg1199Trp	missense_variant	28/29

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VARS1	ENST00000375663.8	c.3595C>T	p.Arg1199Trp	missense_variant	29/30	1	NM_006295.3	P1

Frequencies

GnomAD3 genomes AF: 0.000158 AC: 24 AN: 152210 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000108 AC: 26 AN: 240552 Hom.: 0 AF XY: 0.0000987 AC XY: 13 AN XY: 131712

Gnomad AFR exome AF: 0.0000685

Gnomad AMR exome AF: 0.0000587

Gnomad ASJ exome AF: 0.000309

Gnomad EAS exome AF: 0.0000557

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000168

Gnomad OTH exome AF: 0.000170

GnomAD4 exome AF: 0.000254 AC: 370 AN: 1458684 Hom.: 0 Cov.: 32 AF XY: 0.000236 AC XY: 171 AN XY: 725592

Gnomad4 AFR exome AF: 0.0000897

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.000423

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000312

Gnomad4 OTH exome AF: 0.000116

GnomAD4 genome AF: 0.000158 AC: 24 AN: 152328 Hom.: 0 Cov.: 32 AF XY: 0.000175 AC XY: 13 AN XY: 74484

Gnomad4 AFR AF: 0.000192

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.000865

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000191

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000286 Hom.: 0

Bravo AF: 0.000155

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000739 AC: 4

ExAC AF: 0.000111 AC: 13

EpiCase AF: 0.0000545

EpiControl AF: 0.000178

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 25, 2024

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.42
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Benign	0.21	T
Eigen	Benign	-0.11
Eigen_PC	Benign	-0.13
FATHMM_MKL	Uncertain	0.94	D
M_CAP	Benign	0.052	D
MetaRNN	Uncertain	0.50	D
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	L
MutationTaster	Benign	0.51	D
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-4.3	D
REVEL	Benign	0.23
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0090	D
Polyphen		1.0	D
Vest4		0.59
MVP		0.26
MPC		1.2
ClinPred		0.68	D
GERP RS		3.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.10
gMVP		0.65

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: rs141077941; hg19: chr6-31746875;