rs121908976
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Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1PM2PP5
The ENST00000330775.9(SLC37A4):c.287G>A(p.Trp96Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.0000343 in 1,456,142 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). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 0.000034 ( 0 hom. )
Consequence
SLC37A4
ENST00000330775.9 stop_gained
ENST00000330775.9 stop_gained
Scores
2
1
1
Clinical Significance
Conservation
PhyloP100: 5.57
Genes affected
SLC37A4 (HGNC:4061): (solute carrier family 37 member 4) This gene regulates glucose-6-phosphate transport from the cytoplasm to the lumen of the endoplasmic reticulum, in order to maintain glucose homeostasis. It also plays a role in ATP-mediated calcium sequestration in the lumen of the endoplasmic reticulum. Mutations in this gene have been associated with various forms of glycogen storage disease. Alternative splicing in this gene results in multiple transcript variants.[provided by RefSeq, Aug 2009]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 11 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 11-119028288-C-T is Pathogenic according to our data. Variant chr11-119028288-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 6928.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1, Pathogenic=2}. Variant chr11-119028288-C-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SLC37A4 | NM_001164277.2 | c.287G>A | p.Trp96Ter | stop_gained | 4/11 | ENST00000642844.3 | |
SLC37A4 | NM_001164279.2 | c.68G>A | p.Trp23Ter | stop_gained | 4/11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SLC37A4 | ENST00000330775.9 | c.287G>A | p.Trp96Ter | stop_gained | 3/10 | 5 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
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GnomAD3 exomes AF: 0.00000840 AC: 2AN: 238134Hom.: 0 AF XY: 0.00000775 AC XY: 1AN XY: 129058
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GnomAD4 exome AF: 0.0000343 AC: 50AN: 1456142Hom.: 0 Cov.: 32 AF XY: 0.0000332 AC XY: 24AN XY: 723712
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GnomAD4 genome ? Cov.: 33
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:4Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Glucose-6-phosphate transport defect Pathogenic:3
Likely pathogenic, criteria provided, single submitter | literature only | Counsyl | Dec 01, 2014 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 27, 2023 | This sequence change creates a premature translational stop signal (p.Trp96*) 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). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with glycogen storage disease (PMID: 9758626). ClinVar contains an entry for this variant (Variation ID: 6928). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jan 17, 2023 | - - |
Phosphate transport defect Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Oct 01, 1998 | - - |
Glycogen storage disease, type I Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Oct 31, 2018 | The SLC37A4 c.287G>A (p.Trp96Ter) variant is a stop-gained variant, which was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018) and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score for this variant, it could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change. No publications were found based on this search. Due to the potential impact of stop-gained variants and the lack of clarifying evidence, the p.Trp96Ter variant is classified as a variant of unknown significance but suspicious for pathogenicity for glycogen storage disease type I. - |
Computational scores
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Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Benign
FATHMM_MKL
Uncertain
D
Vest4
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
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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