rs1060499734
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP2PP3_ModeratePP5
The NM_006295.3(VARS1):c.2653C>T(p.Leu885Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,782 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 Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_006295.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
VARS1 | NM_006295.3 | c.2653C>T | p.Leu885Phe | missense_variant | 23/30 | ENST00000375663.8 | |
VARS1 | XM_005249362.3 | c.2656C>T | p.Leu886Phe | missense_variant | 23/30 | ||
VARS1 | XM_047419296.1 | c.2656C>T | p.Leu886Phe | missense_variant | 22/29 | ||
VARS1 | XM_047419297.1 | c.2653C>T | p.Leu885Phe | missense_variant | 22/29 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
VARS1 | ENST00000375663.8 | c.2653C>T | p.Leu885Phe | missense_variant | 23/30 | 1 | NM_006295.3 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461782Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 727202
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
Neurodevelopmental disorder with microcephaly, seizures, and cortical atrophy Pathogenic:1Uncertain:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Aug 20, 2019 | - - |
Uncertain significance, criteria provided, single submitter | curation | Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | May 20, 2024 | The homozygous p.Leu885Phe variant in VARS1 was identified by our study in two siblings with neurodevelopmental disorder with microcephaly, seizures, and cortical atrophy. This variant has also been reported in two individuals with neurodevelopmental disorder with microcephaly, seizures, and cortical atrophy (PMIDs: 26539891, 30755616), and has been identified in 0.02% (1/4148) of Middle Eastern chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP (rs1060499734)). Data from large population studies is insufficient to assess the frequency of this variant. Of the 2 affected individuals, both of those were homozygotes, which increases the likelihood that the p.Leu885Phe variant is pathogenic (PMIDs: 26539891, 30755616). This variant has been reported in ClinVar (Variation ID: 402133) and has been interpreted as likely pathogenic by Baylor-Hopkins CMG and pathogenic by OMIM. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. The number of missense variants reported in VARS1 in the general population is lower than expected, suggesting there is little benign variation in this gene and slightly increasing the possibility that a missense variant in this gene may not be tolerated. In summary, the clinical significance of the p.Leu885Phe variant is uncertain. ACMG/AMP Criteria applied: PM2_Supporting, PM3, PP2 (Richards 2015). - |
Abnormal brain morphology Pathogenic:1
Likely pathogenic, criteria provided, single submitter | research | Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine | - | There is one more families with similar phenotype - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at