chr6-31779170-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP2

The NM_006295.3(VARS1):​c.3523G>A​(p.Gly1175Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Consequence

VARS1
NM_006295.3 missense

Scores

1
9
8

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.12
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in the VARS1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 14 curated pathogenic missense variants (we use a threshold of 10). The gene has 12 curated benign missense variants. Gene score misZ: 2.6849 (below the threshold of 3.09). Trascript score misZ: 3.4812 (above the threshold of 3.09). GenCC associations: The gene is linked to combined oxidative phosphorylation defect type 20, neurodevelopmental disorder with microcephaly, seizures, and cortical atrophy.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
VARS1NM_006295.3 linkc.3523G>A p.Gly1175Ser missense_variant Exon 29 of 30 ENST00000375663.8 NP_006286.1 P26640-1A0A024RCN6
VARS1XM_005249362.3 linkc.3526G>A p.Gly1176Ser missense_variant Exon 29 of 30 XP_005249419.1
VARS1XM_047419296.1 linkc.3526G>A p.Gly1176Ser missense_variant Exon 28 of 29 XP_047275252.1
VARS1XM_047419297.1 linkc.3523G>A p.Gly1175Ser missense_variant Exon 28 of 29 XP_047275253.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
VARS1ENST00000375663.8 linkc.3523G>A p.Gly1175Ser missense_variant Exon 29 of 30 1 NM_006295.3 ENSP00000364815.3 P26640-1
VARS1ENST00000463184.1 linkn.*60G>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
LINK: link

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Aug 19, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.3523G>A (p.G1175S) 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 3523, causing the glycine (G) at amino acid position 1175 to be replaced by a serine (S). 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
Uncertain
0.40
BayesDel_addAF
Benign
-0.093
T
BayesDel_noAF
Benign
-0.37
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Benign
0.13
T
Eigen
Uncertain
0.36
Eigen_PC
Uncertain
0.31
FATHMM_MKL
Uncertain
0.93
D
M_CAP
Benign
0.059
D
MetaRNN
Uncertain
0.65
D
MetaSVM
Benign
-1.2
T
MutationAssessor
Uncertain
2.6
M
PrimateAI
Uncertain
0.72
T
PROVEAN
Pathogenic
-4.5
D
REVEL
Benign
0.24
Sift
Benign
0.045
D
Sift4G
Uncertain
0.057
T
Polyphen
1.0
D
Vest4
0.57
MutPred
0.40
Gain of glycosylation at G1175 (P = 0.0047);
MVP
0.42
MPC
1.3
ClinPred
0.98
D
GERP RS
4.7
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.23
gMVP
0.72

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-31746947; API