rs786204452
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The ENST00000330775.9(SLC37A4):c.742C>T(p.Gln248Ter) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000616 in 1,461,472 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 (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
ENST00000330775.9 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SLC37A4 | NM_001164277.2 | c.742C>T | p.Gln248Ter | stop_gained | 7/11 | ENST00000642844.3 | |
SLC37A4 | NM_001164279.2 | c.523C>T | p.Gln175Ter | stop_gained | 7/11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SLC37A4 | ENST00000330775.9 | c.742C>T | p.Gln248Ter | stop_gained | 6/10 | 5 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 exomes AF: 0.0000241 AC: 6AN: 248734Hom.: 0 AF XY: 0.0000222 AC XY: 3AN XY: 134970
GnomAD4 exome AF: 0.00000616 AC: 9AN: 1461472Hom.: 0 Cov.: 32 AF XY: 0.00000688 AC XY: 5AN XY: 727002
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Glucose-6-phosphate transport defect Pathogenic:6
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 28, 2023 | This sequence change creates a premature translational stop signal (p.Gln248*) in the SLC37A4 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SLC37A4 are known to be pathogenic (PMID: 9758626, 10940311). This variant is present in population databases (rs781784543, gnomAD 0.009%). This premature translational stop signal has been observed in individuals with glycogen storage disease type Ib (PMID: 9758626, 10026167, 18437526). ClinVar contains an entry for this variant (Variation ID: 188762). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jul 28, 2016 | Variant summary: The SLC37A4 c.742C>T (p.Gln248X) variant results in a premature termination codon, predicted to cause a truncated or absent SLC37A4 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. This variant was found in 2/118148 control chromosomes at a frequency of 0.0000169, which does not exceed the estimated maximal expected allele frequency of a pathogenic SLC37A4 variant (0.0012247). This variant has been reported in multiple GSD type 1b patients both homozygously and heterozygously. In addition, one clinical diagnostic laboratory classified this variant as likely pathogenic, without evidence to independently evaluate. Taken together, this variant is classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center | Jul 05, 2023 | PVS1, PM2, PM3 - |
Likely pathogenic, criteria provided, single submitter | literature only | Counsyl | Apr 21, 2014 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 28, 2024 | - - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Mar 09, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jul 20, 2018 | The Q248X pathogenic variant in the SLC37A4 gene has been reported previously in association with glycogen storage disease type 1b when present in the homozygous state or when in trans with another pathogenic variant (Veiga-da-Cunha et al., 1998; Melis et al., 2005; Jun et al., 2014). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The Q248X variant was not observed in approximately 6,100 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. We interpret Q248X as a pathogenic variant. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at