rs587777778
Variant summary
Our verdict is Pathogenic. Variant got 22 ACMG points: 22P and 0B. PS1_Very_StrongPM1PM2PP3_ModeratePP5_Very_Strong
The NM_058179.4(PSAT1):c.296C>T(p.Ala99Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000273 in 1,614,034 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 (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin ClinVar. Synonymous variant affecting the same amino acid position (i.e. A99A) has been classified as Benign.
Frequency
Consequence
NM_058179.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 22 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PSAT1 | NM_058179.4 | c.296C>T | p.Ala99Val | missense_variant | 4/9 | ENST00000376588.4 | |
PSAT1 | NM_021154.5 | c.296C>T | p.Ala99Val | missense_variant | 4/8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PSAT1 | ENST00000376588.4 | c.296C>T | p.Ala99Val | missense_variant | 4/9 | 1 | NM_058179.4 | P1 | |
PSAT1 | ENST00000347159.6 | c.296C>T | p.Ala99Val | missense_variant | 4/8 | 1 |
Frequencies
GnomAD3 genomes ? AF: 0.000184 AC: 28AN: 152160Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000159 AC: 40AN: 251482Hom.: 0 AF XY: 0.000199 AC XY: 27AN XY: 135916
GnomAD4 exome AF: 0.000282 AC: 412AN: 1461874Hom.: 0 Cov.: 30 AF XY: 0.000276 AC XY: 201AN XY: 727238
GnomAD4 genome ? AF: 0.000184 AC: 28AN: 152160Hom.: 0 Cov.: 33 AF XY: 0.000135 AC XY: 10AN XY: 74332
ClinVar
Submissions by phenotype
not provided Pathogenic:2Other:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jul 18, 2023 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Jun 20, 2017 | - - |
not provided, no classification provided | in vivo;research | Dudley Research Group, Pacific Northwest Research Institute | - | - - |
Neu-Laxova syndrome 2 Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Oct 19, 2020 | Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Neu-Laxova syndrome 2 (MIM#616038). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from alanine to valine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD v2 <0.01 for a recessive condition (43 heterozygotes, 0 homozygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated aminotransferase class-V domain (PDB). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as pathogenic and likely pathogenic, in multiple homozygous and compound heterozygous patients with Neu-Laxova syndrome. As a common polymorphism is sometimes found in cis with this variant, it has also been reported as c.296_297delinsTG (ClinVar, PMID: 25152457, PMID: 26960553; PMID: 30293248). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Yeast growth assays demonstrate that this variant significantly impairs growth compared to wildtype (PMID: 32077105). (SP) 1206 - This variant has been shown to be paternally inherited (VCGS #20G001772). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Sep 04, 2014 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at