rs786204477
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Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PM4PP5
The NM_001164279.2(SLC37A4):c.715_716insTGGCTGGCATGA(p.Met235_Met238dup) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000255 in 1,608,924 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000027 ( 0 hom. )
Consequence
SLC37A4
NM_001164279.2 inframe_insertion
NM_001164279.2 inframe_insertion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 1.88
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 Likely_pathogenic. Variant got 7 ACMG points.
PM1
?
In a transmembrane_region Helical (size 20) in uniprot entity G6PT1_HUMAN there are 9 pathogenic changes around while only 0 benign (100%) in NM_001164279.2
PM2
?
Very rare variant in population databases, with high coverage;
PM4
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Nonframeshift variant in NON repetitive region in NM_001164279.2.
PP5
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Variant 11-119026016-G-GTCATGCCAGCCA is Pathogenic according to our data. Variant chr11-119026016-G-GTCATGCCAGCCA is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 188799.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, Likely_pathogenic=2, Uncertain_significance=1}.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SLC37A4 | NM_001164277.2 | c.934_935insTGGCTGGCATGA | p.Met308_Met311dup | inframe_insertion | 9/11 | ENST00000642844.3 | |
SLC37A4 | NM_001164279.2 | c.715_716insTGGCTGGCATGA | p.Met235_Met238dup | inframe_insertion | 9/11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SLC37A4 | ENST00000330775.9 | c.934_935insTGGCTGGCATGA | p.Met308_Met311dup | inframe_insertion | 8/10 | 5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152132Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000415 AC: 1AN: 240832Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 130378
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GnomAD4 exome AF: 0.0000275 AC: 40AN: 1456792Hom.: 0 Cov.: 31 AF XY: 0.0000304 AC XY: 22AN XY: 724102
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GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152132Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74302
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:5Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Glucose-6-phosphate transport defect Pathogenic:3Uncertain:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Oct 01, 1998 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 16, 2024 | - - |
Likely pathogenic, criteria provided, single submitter | literature only | Counsyl | May 21, 2014 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Mar 29, 2022 | This variant, c.923_934dup, results in the insertion of 4 amino acid(s) of the SLC37A4 protein (p.Met308_Met311dup), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs786204477, gnomAD 0.002%). This variant has been observed in individual(s) with glycogen storage disease type Ib (PMID: 9758626, 33977030). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 188799). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
SLC37A4-related disorder Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | May 31, 2023 | The SLC37A4 c.923_934dup12 variant is predicted to result in an in-frame duplication (p.Met308_Met311dup). This variant was reported in at least three individuals with Glycogen storage disease 1b and 1c and in at least two of those patients was this variant was observed in a compound heterozygous state with loss of function variant (Veiga-da-Cunha et al. 1998. PubMed ID: 9758626; Halligan et al. 2021. PubMed ID: 33977030). This variant is reported in 0.0016% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-118896726-G-GTCATGCCAGCCA). This variant is interpreted as likely pathogenic. - |
Phosphate transport defect Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Oct 01, 1998 | - - |
Computational scores
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at