chr11-119026079-G-C

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBS1_Supporting

The NM_001164278.2(SLC37A4):ā€‹c.872C>Gā€‹(p.Ala291Gly) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000107 in 1,586,762 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 10/13 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: š‘“ 0.00055 ( 0 hom., cov: 32)
Exomes š‘“: 0.000061 ( 0 hom. )

Consequence

SLC37A4
NM_001164278.2 missense, splice_region

Scores

2
9

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:2

Conservation

PhyloP100: 1.79
Variant links:
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_benign. Variant got -3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.019008964).
BS1
Variant frequency is greater than expected in population afr. gnomad4_exome allele frequency = 0.0000606 (87/1434508) while in subpopulation AFR AF= 0.00185 (61/32930). AF 95% confidence interval is 0.00148. There are 0 homozygotes in gnomad4_exome. There are 40 alleles in male gnomad4_exome subpopulation. Median coverage is 30. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SLC37A4NM_001164278.2 linkc.872C>G p.Ala291Gly missense_variant, splice_region_variant Exon 9 of 12 NP_001157750.1 O43826-2A0A024R3L1
SLC37A4NM_001164277.2 linkc.872C>G p.Ala291Gly missense_variant, splice_region_variant Exon 9 of 11 NP_001157749.1 O43826-1A0A024R3H9A8K0S7
SLC37A4NM_001164280.2 linkc.872C>G p.Ala291Gly missense_variant, splice_region_variant Exon 7 of 9 NP_001157752.1 O43826-1A0A024R3H9

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SLC37A4ENST00000330775.9 linkc.872C>G p.Ala291Gly missense_variant, splice_region_variant Exon 8 of 10 5 ENSP00000476242.2 U3KPU7

Frequencies

GnomAD3 genomes
AF:
0.000546
AC:
83
AN:
152136
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00174
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000523
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.000957
GnomAD3 exomes
AF:
0.000192
AC:
40
AN:
208402
Hom.:
0
AF XY:
0.000197
AC XY:
22
AN XY:
111666
show subpopulations
Gnomad AFR exome
AF:
0.00193
Gnomad AMR exome
AF:
0.000270
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000661
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000654
Gnomad OTH exome
AF:
0.000188
GnomAD4 exome
AF:
0.0000606
AC:
87
AN:
1434508
Hom.:
0
Cov.:
30
AF XY:
0.0000562
AC XY:
40
AN XY:
711284
show subpopulations
Gnomad4 AFR exome
AF:
0.00185
Gnomad4 AMR exome
AF:
0.000271
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000121
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000820
Gnomad4 OTH exome
AF:
0.0000841
GnomAD4 genome
AF:
0.000545
AC:
83
AN:
152254
Hom.:
0
Cov.:
32
AF XY:
0.000672
AC XY:
50
AN XY:
74436
show subpopulations
Gnomad4 AFR
AF:
0.00173
Gnomad4 AMR
AF:
0.000523
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.000947
Alfa
AF:
0.0000104
Hom.:
0
Bravo
AF:
0.000620
ExAC
AF:
0.000199
AC:
24

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:5Benign:2
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Glucose-6-phosphate transport defect Uncertain:2
Nov 17, 2019
Natera, Inc.
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Jan 23, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 291 of the SLC37A4 protein (p.Ala291Gly). This variant is present in population databases (rs200147602, gnomAD 0.2%). This variant has not been reported in the literature in individuals affected with SLC37A4-related conditions. ClinVar contains an entry for this variant (Variation ID: 969047). 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. -

not provided Uncertain:1Benign:1
Jan 31, 2023
GeneDx
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Oct 21, 2024
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Inborn genetic diseases Uncertain:1
Nov 07, 2022
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The p.A291G variant (also known as c.872C>G), located in coding exon 6 of the SLC37A4 gene, results from a C to G substitution at nucleotide position 872. The alanine at codon 291 is replaced by glycine, an amino acid with similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Glucose-6-phosphate transport defect;C0342749:Phosphate transport defect;C5561986:Congenital disorder of glycosylation, type IIw Uncertain:1
May 18, 2024
Fulgent Genetics, Fulgent Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

SLC37A4-related disorder Benign:1
Jun 25, 2024
PreventionGenetics, part of Exact Sciences
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.11
BayesDel_addAF
Benign
-0.31
T
BayesDel_noAF
Benign
-0.22
CADD
Benign
16
DANN
Benign
0.62
DEOGEN2
Benign
0.12
T;T;T;T
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Uncertain
0.91
.;D;D;D
M_CAP
Benign
0.016
T
MetaRNN
Benign
0.019
T;T;T;T
PrimateAI
Benign
0.42
T
Sift4G
Benign
0.42
T;T;T;T
Vest4
0.33
MVP
0.57
MPC
0.034
GERP RS
3.5
gMVP
0.18

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs200147602; hg19: chr11-118896789; API