rs201036248
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Variant summary
Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM1BP4_StrongBP6BS2
The NM_001164278.2(SLC37A4):c.467C>T(p.Ala156Val) variant causes a missense change. The variant allele was found at a frequency of 0.00237 in 1,611,414 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. 8/13 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.0020 ( 1 hom., cov: 33)
Exomes 𝑓: 0.0024 ( 9 hom. )
Consequence
SLC37A4
NM_001164278.2 missense
NM_001164278.2 missense
Scores
3
8
Clinical Significance
Conservation
PhyloP100: 5.24
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 Benign. Variant got -7 ACMG points.
PM1
In a transmembrane_region Helical (size 20) in uniprot entity G6PT1_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_001164278.2
BP4
Computational evidence support a benign effect (MetaRNN=0.011417329).
BP6
Variant 11-119027787-G-A is Benign according to our data. Variant chr11-119027787-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 215177.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=2, Benign=2}.
BS2
High Homozygotes in GnomAdExome4 at 9 AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SLC37A4 | NM_001164278.2 | c.467C>T | p.Ala156Val | missense_variant | 5/12 | NP_001157750.1 | ||
SLC37A4 | NM_001164277.2 | c.467C>T | p.Ala156Val | missense_variant | 5/11 | NP_001157749.1 | ||
SLC37A4 | NM_001164280.2 | c.467C>T | p.Ala156Val | missense_variant | 3/9 | NP_001157752.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SLC37A4 | ENST00000330775.9 | c.467C>T | p.Ala156Val | missense_variant | 4/10 | 5 | ENSP00000476242.2 |
Frequencies
GnomAD3 genomes AF: 0.00205 AC: 312AN: 152244Hom.: 1 Cov.: 33
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GnomAD3 exomes AF: 0.00166 AC: 403AN: 243018Hom.: 2 AF XY: 0.00163 AC XY: 215AN XY: 131964
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GnomAD4 exome AF: 0.00241 AC: 3514AN: 1459052Hom.: 9 Cov.: 34 AF XY: 0.00240 AC XY: 1744AN XY: 725606
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GnomAD4 genome AF: 0.00205 AC: 312AN: 152362Hom.: 1 Cov.: 33 AF XY: 0.00209 AC XY: 156AN XY: 74504
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:5
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Glucose-6-phosphate transport defect Benign:2
Likely benign, no assertion criteria provided | clinical testing | Natera, Inc. | Apr 03, 2020 | - - |
Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 31, 2024 | - - |
not provided Benign:2
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Apr 13, 2020 | This variant is associated with the following publications: (PMID: 22899091) - |
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Nov 01, 2024 | SLC37A4: BS2 - |
Glycogen storage disease, type I Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
Glucose-6-phosphate transport defect;C0342749:Phosphate transport defect Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago | Oct 01, 2021 | SLC37A4 NM_001164277.1 exon 4 p.Ala156Val (c.467C>T): This variant has been reported in the literature in 1 individual with features suggestive of a glycogen storage disease; of note, it was one of three SLC37A4 variants identified in this individual, determined to be in cis with one variant and of unknown phase with the other (Wang 2013 PMID:22899091). This variant is present in 0.4% (42/10624) of Finnish alleles and in 1 homozygote in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/11-119027787-G-A?dataset=gnomad_r3). This variant is present in ClinVar (Variation ID:215177). Evolutionary conservation and computational predictive tools for this variant are unclear. Splice prediction tools suggest that this variant may affect splicing. However, further studies are needed to understand its impact. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. - |
not specified Benign:1
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 02, 2023 | Variant summary: SLC37A4 c.467C>T (p.Ala156Val) results in a non-conservative amino acid change located in the Major facilitator superfamily domain (IPR020846) of the encoded protein sequence. One of two in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0019 in 274424 control chromosomes, including 2 homozygotes (gnomAD). The variant was found predominantly at a frequency of 0.003 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 2.5 fold of the estimated maximal expected allele frequency for a pathogenic variant in SLC37A4 causing Glycogen Storage Disease Type Ib (0.0012), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.467C>T has been reported in the literature occuring in cis with variant c.572C>T [p.Pro191Arg] in one individual affected with Glycogen Storage Disease Type Ib (Wang_2013). This report does not provide unequivocal conclusions about association of the variant with Glycogen Storage Disease Type Ib. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 22899091). Six ClinVar submitters have assessed the variant since 2014: three classified the variant as uncertain significance, two as likely benign, and one as benign. Based on the evidence outlined above, the variant was classified as benign. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
DEOGEN2
Benign
T;T;T;T
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
.;D;D;D
M_CAP
Benign
T
MetaRNN
Benign
T;T;T;T
PrimateAI
Uncertain
T
Sift4G
Benign
T;T;T;T
Vest4
MVP
MPC
0.027
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
gMVP
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