6-31779071-G-A
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Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_ModeratePM2PP5_Very_Strong
The NM_006295.3(VARS1):c.3622C>T(p.Arg1208*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000868 in 1,612,382 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000082 ( 0 hom. )
Consequence
VARS1
NM_006295.3 stop_gained
NM_006295.3 stop_gained
Scores
2
1
4
Clinical Significance
Conservation
PhyloP100: 0.818
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 Pathogenic. Variant got 12 ACMG points.
PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0456 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 6-31779071-G-A is Pathogenic according to our data. Variant chr6-31779071-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 873441.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| VARS1 | NM_006295.3 | c.3622C>T | p.Arg1208* | stop_gained | 29/30 | ENST00000375663.8 | NP_006286.1 | |
| VARS1 | XM_005249362.3 | c.3625C>T | p.Arg1209* | stop_gained | 29/30 | XP_005249419.1 | ||
| VARS1 | XM_047419296.1 | c.3625C>T | p.Arg1209* | stop_gained | 28/29 | XP_047275252.1 | ||
| VARS1 | XM_047419297.1 | c.3622C>T | p.Arg1208* | stop_gained | 28/29 | XP_047275253.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| VARS1 | ENST00000375663.8 | c.3622C>T | p.Arg1208* | stop_gained | 29/30 | 1 | NM_006295.3 | ENSP00000364815.3 |
Frequencies
GnomAD3 genomes 0.0000131 AC: 2AN: 152216Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000205 AC: 5AN: 243740Hom.: 0 AF XY: 0.0000225 AC XY: 3AN XY: 133190
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GnomAD4 exome AF: 0.00000822 AC: 12AN: 1460166Hom.: 0 Cov.: 32 AF XY: 0.00000964 AC XY: 7AN XY: 726382
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GnomAD4 genome 0.0000131 AC: 2AN: 152216Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74374
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Neurodevelopmental disorder with microcephaly, seizures, and cortical atrophy Pathogenic:2
| Likely pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Oct 01, 2019 | The variant was confirmed as compound heterozygous with a variant of uncertain significance (NM_006295.2: c.1014G>T). - |
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 24, 2023 | Variant summary: VARS1 c.3622C>T (p.Arg1208X) results in a premature termination codon, predicted to cause absence of the protein due to nonsense mediated decay, which is a commonly known mechanism for disease. The variant allele was found at a frequency of 2.1e-05 in 243740 control chromosomes (gnomAD). c.3622C>T has been reported in the literature in an individual(s) affected with a Neurodevelopmental Disorder (Halfmeyer_2022). The following publication has been ascertained in the context of this evaluation (PMID: 36672771). One submitter has cited a clinical-significance assessment for this variant to ClinVar after 2014 and has classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Computational scores
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Name
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BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
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Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
D
Vest4
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at