chr6-31779200-C-T

Position:

• chr6-31779200-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.3493G>A​(p.Val1165Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: VARS1 NM_006295.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.390

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]

VARS1 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), VARS1. . Gene score misZ 2.6849 (greater than the threshold 3.09). Trascript score misZ 3.4812 (greater than threshold 3.09). GenCC has associacion of gene with combined oxidative phosphorylation defect type 20, neurodevelopmental disorder with microcephaly, seizures, and cortical atrophy.
• BP4: Computational evidence support a benign effect (MetaRNN=0.10891116).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VARS1	NM_006295.3	c.3493G>A	p.Val1165Ile	missense_variant	29/30	ENST00000375663.8	NP_006286.1
VARS1	XM_005249362.3	c.3496G>A	p.Val1166Ile	missense_variant	29/30		XP_005249419.1
VARS1	XM_047419296.1	c.3496G>A	p.Val1166Ile	missense_variant	28/29		XP_047275252.1
VARS1	XM_047419297.1	c.3493G>A	p.Val1165Ile	missense_variant	28/29		XP_047275253.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VARS1	ENST00000375663.8	c.3493G>A	p.Val1165Ile	missense_variant	29/30	1	NM_006295.3	ENSP00000364815.3
VARS1	ENST00000463184.1	n.*30G>A		downstream_gene_variant		2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 27, 2024

The c.3493G>A (p.V1165I) alteration is located in exon 29 (coding exon 28) of the VARS gene. This alteration results from a G to A substitution at nucleotide position 3493, causing the valine (V) at amino acid position 1165 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	16
DANN	Benign	0.87
DEOGEN2	Benign	0.0066	T
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.40
FATHMM_MKL	Benign	0.40	N
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.27	N
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-0.19	N
REVEL	Benign	0.086
Sift	Benign	0.47	T
Sift4G	Benign	0.42	T
Polyphen		0.0010	B
Vest4		0.12
MutPred		0.36		Gain of sheet (P = 0.0085);
MVP		0.18
MPC		0.37
ClinPred		0.053	T
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.025
gMVP		0.16

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: rs1331528732; hg19: chr6-31746977;