6-31779200-C-T

Variant names:

• chr6-31779200-C-T
• rs1331528732
• NM_006295.3:c.3493G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 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. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• 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
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• neurodevelopmental disorder with microcephaly, seizures, and cortical atrophy

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

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10891116).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006295.3. 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
	VARS1	NM_006295.3	MANE Select	c.3493G>A	p.Val1165Ile	missense	Exon 29 of 30	NP_006286.1	P26640-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VARS1	ENST00000375663.8	TSL:1 MANE Select	c.3493G>A	p.Val1165Ile	missense	Exon 29 of 30	ENSP00000364815.3	P26640-1
	VARS1	ENST00000851851.1		c.3538G>A	p.Val1180Ile	missense	Exon 29 of 30	ENSP00000521910.1
	VARS1	ENST00000851849.1		c.3532G>A	p.Val1178Ile	missense	Exon 29 of 30	ENSP00000521908.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00 AC: 0 AN: 227310 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		0.39
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
Mutation Taster		=100/0	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: rs1331528732; hg19: chr6-31746977;